Alpha-hydroxy-beta-azido-tetrazoles

ABSTRACT

Alpha-hydroxy-beta-azido tetrazole compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     a process for manufacturing alpha-hydroxy-beta-azido tetrazoles of formula (I), and their use for synthesizing new compounds, e.g. in “click” chemistry.

FIELD OF INVENTION

The present invention pertains to chemistry, especially to organicchemistry and to the synthesis of organic compounds.

The present invention relates to alpha, beta-substituted tetrazolecompounds, especially alpha-hydroxy-beta-azido-tetrazole compounds, andtheir manufacturing process. The present invention further relates tothe use of alpha-hydroxy-beta-azido-tetrazoles for synthesizing newcompounds, especially but not limitatively in “click” chemistry.

BACKGROUND OF INVENTION

Tetrazoles have found applications in various domains including materialscience, energetic materials, coordination chemistry, organic synthesis,and especially medicinal chemistry, due to the fact that 5-substitutedtetrazoles (5-ST) are bioisosteres of carboxylic acids. Therefore, thereis a need of novel methods for introducing a tetrazole functional groupin compounds, e.g. in organic molecules.

The 1,3-dipolar cycloaddition (Huisgen reaction) of azides and alkynesleads to 5-membered triazole heterocycles and has gained considerableinterest in the field of organic synthesis since the development ofcopper (I)-catalysed procedures by Medal and Tomøe. Copper-catalysedazide-alkyne cycloaddition (CuAAC) is a well-known “click” reaction,which is very general and has many attractive features, including: highor quantitative yields, robustness, insensibility, orthogonality, andcompatibly with biological and polymerization conditions (Meldal, M. andTomøe, C. W., Chemical Reviews 2008, Vol. 108, pp. 2952-3015.). Aparticularly advantageous aspect of CuAAC is that it allows orthogonalligation reactions, which means that a dedicated set of reactionconditions will lead to a ligation reaction occurring specifically on afunctional group of a molecule, without affecting the others.

Due to the popularity of CuAAC reaction, many libraries of compatibleazides and alkynes are available. However, there is a need fromimprovement of the selectivity of CuAAC reactions and/or reduction ofthe number of steps for the synthesis of complex molecules. Therefore,there is still a need for novel reactants having specific featuresadvantageous for CuAAC and presenting a variety of reactive groups,especially tetrazoles groups. There is also a need for reactantscomprising “latent” or “hidden” functional groups, i.e. groups whichwill not react in CuAAC conditions, but may be easily converted to azideor alkyne when another reactive group is required, thus allowingsequential CuAAC reactions.

The applicant surprisingly established thatalpha-hydroxy-beta-azido-tetrazoles could be useful molecular scaffoldsfor chemical synthesis, in particular for sequenced synthesis.Therefore, the applicant conceived and successfully reduced to practicethe manufacture of alpha-hydroxy-beta-azido-tetrazoles and their use asreactant, especially in “click” reactions.

SUMMARY

In a first aspect, the invention relates to an alpha-hydroxy-beta-azidotetrazole compound of formula (I):

wherein R¹ and R² are each independently hydrogen, hydrocarbyl, aryl,heteroaryl, hydrocarbylaryl, arylhydrocarbyl, hydrocarbylheteroaryl, orheteroarylhydrocarbyl groups; or R¹ and R² form together a group beinghydrocarbyl, aryl, heteroaryl, hydrocarbylaryl, arylhydrocarbyl,hydrocarbylheteroaryl or heteroarylhydrocarbyl;

-   -   wherein the group is optionally substituted by at least one        hydrocarbyl, heteroaryl, oxo, hydroxyl, amido, amino, nitro,        carboxylo, formyl, halo, thioxo or sulfhydryl;    -   wherein the group is optionally interrupted or terminated by at        least one group being —O—; —S—; or —NR^(N)— wherein R^(N) is        hydrogen, hydrocarbyl, aryl, or a combination thereof; and    -   wherein the nitrogen or sulfur atoms substituting or comprised        in the group are optionally oxidized;        and stereoisomers thereof; and salts thereof; and solvates        thereof.

According to an embodiment, R¹ and R² are each independently selectedfrom the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl,alkylaryl, arylalkyl, alkenylaryl, and arylalkenyl groups; wherein thegroups are optionally substituted by at least one group selected fromthe group consisting of hydroxyl, alkyl, alkenyl, aryl, alkylaryl,arylalkyl, amino, nitro, halo and sulfhydryl; and wherein the groups areoptionally interrupted or terminated by at least one group selected fromthe group consisting of —O—; —S—; and —NR^(N)— wherein R^(N) is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, aryl, and acombination thereof.

According to an embodiment, R¹ and R² are each independently selectedfrom the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl,alkylaryl and alkenylaryl groups; wherein the groups are optionallysubstituted by at least one group selected from the group consisting ofhydroxyl, alkyl, amino, nitro, halo and sulfhydryl; and wherein thegroups are optionally interrupted or terminated by at least one groupselected from the group consisting of —O—; —S—; and —NR^(N)— whereinR^(N) is selected from the group consisting of hydrogen, alkyl, alkenyl,aryl, alkylaryl, and arylalkyl.

According to an embodiment, R¹ and R² are each independently selectedfrom the group consisting of hydrogen, alkyl, aryl and alkenylarylgroups; and the groups are optionally substituted by at least one halogroup.

According to an embodiment, R¹ and R² form together a group selectedfrom the group consisting of alkyl, alkenyl, aryl, alkylaryl, arylalkyl,alkenylaryl and arylalkenyl; wherein the group is optionally substitutedby at least one group selected from the group consisting of hydroxyl,alkyl, alkenyl, aryl, alkylaryl, arylalkyl, amino, nitro, halo andsulfhydryl; and wherein the group is optionally interrupted orterminated by at least one group selected from the group consisting of—O—; —S—; and —NR^(N)— wherein R^(N) is selected from the groupconsisting of hydrogen, alkyl, alkenyl, aryl, and a combination thereof.

According to an embodiment, R¹ and R² form together a group selectedfrom the group consisting of alkyl, alkylaryl and arylalkyl; wherein thegroup is optionally substituted by at least one group selected from thegroup consisting of hydroxyl, alkyl, amino, nitro and halo; and whereinthe group is optionally interrupted or terminated by at least one groupselected from the group consisting of —O— and —NR^(N)— wherein R^(N) isselected from the group consisting of hydrogen, alkyl, alkenyl, aryl,alkylaryl, and arylalkyl.

According to an embodiment, R¹ and R² form together a group selectedfrom the group consisting of alkyl and aryl.

According to an embodiment, the alpha-hydroxy-beta-azido-tetrazole isselected from the group consisting of:2-azido-2-phenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;2-azido-2-(naphthalen-2-yl)-1-(1H-tetrazol-5-yl)ethan-1-ol;2-azido-2-(4-chlorophenyl)-1-(1H-tetrazol-5-yl)ethan-1-ol;2-azido-1-(1H-tetrazol-5-yl)-2-(thiophen-2-yl)ethan-1-ol;2-azido-4-phenyl-1-(1H-tetrazol-5-yl)but-3-en-1-ol;2-azido-1-(1H-tetrazol-5-yl)nonan-1-ol;2-azido-2-ethyl-1-(1H-tetrazol-5-yl)butan-1-ol; and2-azido-2,2-diphenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;(1-azidocyclopentyl)(1H-tetrazol-5-yl)methanol;(1-azidocyclohexyl)(1H-tetrazol-5-yl)methanol; (1-azidocycloheptyl)(1H-tetrazol-5-yl)methanol;(1-azidocyclooctyl)(1H-tetrazol-5-yl)methanol; or(9-azido-9H-fluoren-9-yl)(1H-tetrazol-5-yl)methanol.

In a second aspect, the invention relates to a process for manufacturinga compound of formula (I) according to claim 1 comprising: starting froman epoxynitrile of formula (II):

and performing the following steps:

-   -   (a) reacting compound (II) with an azide in presence of an        organometallic catalyst, and    -   (b) performing an hydrolysis reaction to afford compound (I).

According to an embodiment, the azide is trimethylsilyl azide. Accordingto an embodiment, the organometallic catalyst is dibutyltin oxide.According to an embodiment, step (a) is executed in a solvent, saidsolvent being toluene. According to an embodiment, step (a) is executedat 60° C. during 18 h. According to an embodiment, step (b) ofhydrolysis is acidic hydrolysis.

In others aspects, the invention relates to analpha-hydroxy-beta-triazole-tetrazole compound of formula (III):

wherein R¹ and R² are each independently hydrogen, hydrocarbyl, aryl,heteroaryl, hydrocarbylaryl, arylhydrocarbyl, hydrocarbylheteroaryl, orheteroarylhydrocarbyl groups; or R¹ and R² form together a group beinghydrocarbyl, aryl, heteroaryl, hydrocarbylaryl, arylhydrocarbyl,hydrocarbylheteroaryl, or heteroarylhydrocarbyl;

-   -   wherein the groups are optionally substituted by at least one        group being hydrocarbyl, aryl, heteroaryl, oxo, hydroxyl, amido,        amino, nitro, carboxylo, formyl, halo, thioxo or sulfhydryl;    -   wherein the groups are optionally interrupted or terminated by        at least one group being —O—; —S—; and —NR^(N)— wherein R^(N) is        hydrogen, hydrocarbyl, aryl, or a combination thereof;    -   wherein the nitrogen or sulfur atoms substituting or comprised        in the group are optionally oxidized; and        wherein R³ is hydrogen, an organic group or an organic molecule;        and stereoisomers thereof; and salts thereof; and solvates        thereof.

According to an embodiment, R³ is hydrogen, hydroxyl, amido, amino,cyano, tetrazolyl, triazolyl, nitro, borono, carboxylo, formyl, halo,haloformyl, phosphono, phosphate or sulfhydryl.

According to an embodiment, R³ is hydrogen, hydrocarbyl, aryl,heteroaryl, hydrocarbylaryl, arylhydrocarbyl, hydrocarbylheteroaryl, orheteroarylhydrocarbyl; wherein the group is optionally substituted by atleast one group being hydrocarbyl, heteroaryl, oxo, hydroxyl, amido,amino, cyano, tetrazolyl, triazolyl, nitro, carboxylo, formyl, halo,thioxo or sulfhydryl; and wherein the group is optionally interrupted orterminated by at least one group being —O—; —S—; and —NR^(N)— whereinR^(N) is hydrogen, hydrocarbyl, aryl, or a combination thereof; andwherein the nitrogen or sulfur atoms substituting or comprised in thegroup are optionally oxidized.

According to an embodiment, R³ is a carbohydrate, an amino acid, apeptide or a nucleoside.

According to an embodiment, R³ is selected from the group consisting ofalkyl, alkenyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkenylaryl,arylalkenyl, alkylheteroaryl, and heteroarylalkyl groups; wherein thegroup is optionally substituted by at least one group selected from thegroup consisting of alkyl, alkenyl, aryl, heteroaryl, alkylaryl,arylalkyl, oxo, hydroxyl, amido, amino, tetrazolyl, triazolyl, nitro,carboxylo, formyl, halo, thioxo and sulfhydryl; and the group isoptionally interrupted or terminated by at least one group selected fromthe group consisting of —O—; —S—; and —NR^(N)— wherein R^(N) is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, aryl, and acombination thereof.

According to an embodiment, the alpha-hydroxy-beta-triazolo-tetrazole isselected from the group consisting of:(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclohexyl)(1H-tetrazol-5-yl)methanol;(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cycloheptyl)(1H-tetrazol-5-yl)methanol;(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)(1H-tetrazol-5-yl)methanol;tert-butyl1-(1-(hydroxy(1H-tetrazol-5-yl)methyl)cyclooctyl)-1H-1,2,3-triazole-4-carboxylate;(1-(4-(3-chloropropyl)-1H-1,2,3-triazol-1-yl)cyclooctyl)(1H-tetrazol-5-yl)methanol;2-(1-(1-(hydroxy(1H-tetrazol-5-yl)methyl)cyclooctyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol;2-ethyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-1-(1H-tetrazol-5-yl)butan-1-ol;2-(4-hexyl-1H-1,2,3-triazol-1-yl)-2-phenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;2-(4-hexyl-1H-1,2,3-triazol-1-yl)-2,2-diphenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;2-(4-(3-chloropropyl)-1H-1,2,3-triazol-1-yl)-2,2-diphenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;or tert-butyl1-(2-hydroxy-1,1-diphenyl-2-(1H-tetrazol-5-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate.

In others aspects, the invention relates to a triazole alkyne of formula(IV):

wherein R¹ and R² are each independently groups as previously disclosed;or R¹ and R² form together a group as previously disclosed; and R³ is agroup as previously disclosed; and stereoisomers thereof; and saltsthereof; and solvates thereof.

In others aspects, the invention relates to reactions, especially CuAACreactions, wherein compounds (I), (III) and/or (IV) are used asreactants.

Definitions

In the present invention, the following terms have the followingmeanings:

-   -   “about” preceding a figure means plus or less 10% of the value        of said figure.    -   “alkyl” refers to a linear, cyclic or branched saturated        hydrocarbon chain of general formula —C_(n)H_(2n+1) wherein n is        a number greater than or equal to 1, typically containing 1 to        16 carbon atoms, preferably 1 to 12 carbon atoms, more        preferably 1 to 8 carbon atoms. When concerning a group being        bounded twice to the same carbon atom, “alkyl” also refers to an        alkylenyl derived from an alkyl by removal of a hydrogen atom.        Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl,        butyl, pentyl, hexyl, cyclopentyl and 2-ethylcyclohexyl.    -   “alkenyl” refers to a linear, cyclic or branched unsaturated        hydrocarbon chain, typically containing 1 to 16 carbon atoms,        preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon        atoms, wherein the unsaturation arises from the presence of one        or more carbon-carbon double bonds. When concerning a group        being bounded twice to the same carbon atom, “alkenyl” also        refers to an alkenylenyl derived from an alkenyl by removal of a        hydrogen atom. Examples of alkenyl groups are propenyl, butenyl,        hexenyl and 3-ethylcyclohex-2-enyl.    -   “alkynyl” refers to a linear, cyclic or branched unsaturated        hydrocarbon chain, typically containing 1 to 16 carbon atoms,        preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon        atoms, wherein the unsaturation arises from the presence of one        or more carbon-carbon triple bonds. When concerning a group        being bounded twice to the same carbon atom, “alkynyl” also        refers to an alkynylenyl derived from an alkynyl by removal of a        hydrogen atom. Examples of alkynyl groups are propynyl, butynyl,        hexynyl and 3-ethylcyclohex-2-ynyl.    -   “amido” refers to —C(═O)—NH₂ group.    -   “amino” refers to —NH₂ group.    -   “aryl” refers to a polyunsaturated, aromatic hydrocarbon chain        having a single ring (i.e. phenyl) or multiple rings fused        together (e.g. naphtyl) or linked covalently, wherein at least        one ring is aromatic, typically containing 5 to 16 carbon atoms,        preferably 5 to 10 carbon atoms, more preferably 5 or 6 carbon        atoms. “Aryl” also refers to the partially hydrogenated        derivatives of the carbocyclic systems enumerated herein.        Examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5-        or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl,        1-2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1-        or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or        8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl,        1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl.    -   “azide” refers to a molecule comprising the azido group.    -   “azido” refers to —N₃ (—N═N⁽⁺⁾═N⁽⁻⁾) group.    -   “borono” refers to —B(OH)₂ group.    -   “carboxylo” refers to carboxylic acid —COOH group.    -   “cyano” or “carbonitrile” refers to —C≡N group.    -   “cycloalkyl”, “cycloalkenyl” and “cycloalkynyl” respectively        refers to a cyclic or polycyclic alkyl, alkenyl and alkynyl        group, typically containing 5 to 16 atoms, optionally branched.        Examples of cycloalkyl are cyclopropyl, cyclopentyl and        cyclohexyl.    -   “hydrocarbyl” refers to any alkyl, alkenyl or alkynyl group as        defined above. Unless otherwise stated, any term defined in this        section which include this term “hydrocarbyl” also define every        corresponding term wherein “hydrocarbyl” is substituted by        “alkyl”, “alkenyl” or “alkynyl”. For example, “halohydrocarbyl”        as defined hereafter define simultaneously by similarity        “haloalkyl”, “haloalkenyl” and “haloalkynyl”.    -   “heteroaryl” refers to an aryl group as defined above, wherein        one or more carbon atoms in one or more aromatic rings are        replaced by oxygen, nitrogen or sulfur atoms, and where the        nitrogen and sulfur heteroatoms may optionally be oxidized and        the nitrogen heteroatoms may optionally be quaternized.        Non-limiting examples of such heteroaryl are pyrrolyl, furanyl,        thiophenyl and pyrazolyl.    -   “hydrocarbylaryl” and “arylhydrocarbyl” respectively refers to        an aryl group substituted by, or fused with, a hydrocarbyl group        and to a hydrocarbyl group substituted by, or fused with, an        aryl group.    -   “hydrocarbylheteroaryl” and “heteroarylhydrocarbyl” respectively        refers to a heteroaryl group substituted by, or fused with, a        hydrocarbyl group and to a hydrocarbyl group substituted by, or        fused with, a heteroaryl group.    -   “aryloxyl” refers to —O-aryl group.    -   “hydrocarbyloxyl” refers to —O-hydrocarbyl group.    -   “haloaryl” refers to an aryl group as defined above, further        comprising at least one halo group.    -   “halohydrocarbyl” refers to a hydrocarbyl group as defined        above, further comprising at least one halo group.    -   “formyl” refers to aldehyde —CHO group.    -   “halo” refers to fluoride, chloride, bromide or iodide atoms.    -   “haloformyl” refers to —C(═O)X group, wherein X is halo group as        defined above.    -   “hydroxyl” refers to —OH group.    -   “nitro” refers to —NO₂ group.    -   “nitrile” refers to a molecule comprising the cyano group.    -   “oxo” refers to ═O group, i.e. an oxygen atom forming a double        bond with a carbon atom.    -   “phosphono” refers to —P(═O)(OH)₂ group.    -   “phosphato” refers to —O—P(═O)(OH)₂ group.    -   “prodrug” refers to derivatives of a biologically active drug        compound, such as for example amides, whose in vivo        biotransformation product generates the biologically active        drug. Prodrugs are generally characterized by increased        bio-availability and are readily metabolized into biologically        active compounds in vivo.    -   “protective group” refers to a functional group that masks the        characteristic reactivity of another group to which it can later        be converted. Examples of protecting groups are acetyl (Ac),        benzoyl (Bz), tert-butyloxycarbonyl (BOC), carbobenzoyloxy        (Cbz), p-methoxybenzyl ether (PMB), silyl ethers such as        trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS) and        tetrahydropyranyl (THP).    -   “solvate” refers to a compound that contains stoichiometric or        sub-stoichiometric amounts of one or more solvent molecule such        as ethanol. The term “hydrate” refers to when the solvent is        water.    -   “sulfhydryl” refers to —SH group.    -   “tetrazole” refers to a molecule comprising the tetrazolo group.    -   “tetrazolo” refers to a 5-member heterocyclic group, consisting        of a ring of four nitrogen and one carbon atom of general        formula CRR′N₄, wherein R and R′ are either hydrogen or other        groups.    -   “tetrazolyl” refers to the 5-member heterocyclic group —CHN₄.    -   “triazole” refers to a molecule comprising the triazolo group.    -   “triazolo” refers to a 5-member heterocyclic group, consisting        of a ring of three nitrogen and two carbon atom, of general        formula C₂RR′R″N₃., wherein R, R′ and R″ are either hydrogen or        other groups.    -   “triazolyl” refers to the 5-member heterocyclic group —CH₂N₃.    -   “thioxo” refers to ═S group, i.e. a sulfur atom forming a double        bond with a carbon atom.

In the present invention, the following abbreviations have the followingmeanings:

-   -   “Ac” refers to acetyl group —C(═O)CH₃.    -   “Bu₂SnO” refers to dibutyltin oxide (C₄H₉)₂Sn═O [No. CAS:        818-08-6]    -   “CuAAC” refers to a copper-catalysed azide-alkyne cycloaddition        reaction.    -   “EDC” refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide        [No. CAS: 1892-57-5].    -   “Et” refers to ethyl —C₂H₅.    -   “EtOAc” refers to ethyl acetate [No. CAS: 141-78-6].    -   “DCC” refers to N,N′-dicyclohexylcarbodiimide [No. CAS:        538-75-0].    -   “DIC” refers to N, N′-diisopropylcarbodiimide [No. CAS:        693-13-0].    -   “NaAs” refers to sodium ascorbate [No. CAS: 134-03-2 (L)].    -   “Ph” refers to phenyl —C₆H₅.    -   “TBTA” refers to tris(benzyltriazolylmethyl)amine [No. CAS:        510758-28-8].    -   “TMSN₃” refers to trimethylsilyl azide (CH₃)₃SiN₃ [No. CAS:        4648-54-8].

DETAILED DESCRIPTION Alpha-Hydroxy-Beta-Azido Tetrazoles

In its first aspect, the invention relates to alpha-hydroxy-beta-azidotetrazoles of formula (I):

wherein R¹ and R² are each independently hydrogen, hydrocarbyl, aryl,heteroaryl, hydrocarbylaryl, arylhydrocarbyl, hydrocarbylheteroaryl, orheteroarylhydrocarbyl groups;orR¹ and R² form together a group being hydrocarbyl, aryl, heteroaryl,hydrocarbylaryl, arylhydrocarbyl, hydrocarbylheteroaryl, orheteroarylhydrocarbyl; andthe group is optionally substituted by at least one group beinghydrocarbyl, aryl, heteroaryl, oxo, hydroxyl, amido, amino, azido,cyano, nitro, borono, carboxylo, formyl, halo, haloformyl, phosphono,phosphato, thioxo or sulfhydryl; andthe group is optionally interrupted or terminated by at least one groupbeing —B(OR^(B))— with R^(B) being hydrogen, hydrocarbyl, aryl or acombination thereof; —O—; —PR^(P)— with R^(P) being hydrogen,hydrocarbyl, aryl or a combination thereof; —P(OR^(OP))— with R^(OP)being hydrogen, hydrocarbyl, aryl or a combination thereof; —S—;—NR^(N)— with R^(N) being hydrogen, hydrocarbyl, aryl, or a combinationthereof; or a combination thereof; andthe nitrogen, phosphorus or sulfur atoms substituting or comprised inthe group are optionally oxidized.

The invention also relates to any stereoisomers, salts, solvates, andprodrugs of a compound of formula (I), including quaternary ammoniumsalts.

The compounds of the invention may contain one or more asymmetric centerand may thus exist as different stereoisomeric forms. Accordingly, thepresent invention includes all possible stereoisomers and includes notonly racemic compounds but the individual enantiomers and theirnon-racemic mixtures as well. When a compound is desired as a singleenantiomer, such may be obtained by stereospecific synthesis, byresolution of the final product or any convenient intermediate, or bychiral chromatographic methods as each are known in the art. Resolutionof the final product, an intermediate, or a starting material may beperformed by any suitable method known in the art.

The compounds of the invention may be in the form of salts. Salts of thecompounds of the invention include the acid addition and base saltsthereof. Suitable acid addition salts are formed from acids. Examplesinclude the acetate, adipate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, cams ylate, citrate,cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen, phosphate/dihydrogen, phosphate, pyroglutamate,saccharate, stearate, succinate, tannate, tartrate, tosylate,trifluoroacetate and xinofoate salts. Suitable base salts are formedfrom bases. Examples include the aluminium, arginine, benzathine,calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium,meglumine, olamine, potassium, sodium, tromethamine,2-(diethylamino)ethanol, ethanolamine, morpholine,4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids andbases may also be formed, for example, hemisulphate and hemicalciumsalts. When the compounds of the invention contain an acidic group aswell as a basic group the compounds of the invention may also forminternal salts, and such compounds are within the scope of theinvention. When the compounds of the invention contain ahydrogen-donating heteroatom (e.g. NH), the invention also covers saltsand/or isomers formed by transfer of said hydrogen atom to a basic groupor atom within the molecule. Preferred salts includehydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate,nitrate, citrate, and acetate.

Salts of compounds of the invention may be prepared by one or more ofthese methods:

-   -   (i) by reacting the compound of the invention with the desired        acid;    -   (ii) by reacting the compound of the invention with the desired        base;    -   (iii) by removing an acid- or base-labile protecting group from        a suitable precursor of the compound of the invention or by        ring-opening a suitable cyclic precursor, for example, a lactone        or lactam, using the desired acid; or    -   (iv) by converting one salt of the compound of the invention to        another by reaction with an appropriate acid or by means of a        suitable ion exchange column.

Optionally, one or more alkene, alkyne, oxo, hydroxyl, amido, amino,azido, nitro, borono, carboxylo, formyl, halo, haloformyl, phosphono,phosphato, thioxo or sulfhydryl being present in compound (I) isprotected by any suitable protecting group known by a skilled person ofthe art.

According to an embodiment, R¹ and R² are each independently hydrogen,hydrocarbyl, aryl, heteroaryl, hydrocarbylaryl, arylhydrocarbyl,hydrocarbylheteroaryl, or heteroarylhydrocarbyl groups; and

the groups are optionally substituted by at least one group beinghydrocarbyl, aryl, heteroaryl, oxo, hydroxyl, amido, amino, nitro,carboxylo, formyl, halo, thioxo or sulfhydryl; andthe groups are optionally interrupted or terminated by at least onegroup being —O—; —S—; and —NR^(N)— with R^(N) being hydrogen,hydrocarbyl, aryl, or a combination thereof; and the nitrogen or sulfuratoms substituting or comprised in the groups are optionally oxidized.

According to a specific embodiment, R¹ and R² are each independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, aryl,heteroaryl, alkylaryl, arylalkyl, alkenylaryl, and arylalkenyl groups;

the groups are optionally substituted by at least one group selectedfrom the group consisting of hydroxyl, alkyl, alkenyl, aryl, alkylaryl,arylalkyl, amino, nitro, halo and sulfhydryl; andthe groups are optionally interrupted or terminated by at least onegroup selected from the group consisting of —O—; —S—; and —NR^(N)— withR^(N) being selected from the group consisting of hydrogen, alkyl,alkenyl, aryl, and a combination thereof.

According to a more specific embodiment, R¹ and R² are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, aryl, heteroaryl, alkylaryl and alkenylaryl groups; and thegroups are optionally substituted by at least one group selected fromthe group consisting of hydroxyl, alkyl, amino, nitro, halo andsulfhydryl; and the groups are optionally interrupted or terminated byat least one group selected from the group consisting of —O—; —S—; and—NR^(N)— with R^(N) being selected from the group consisting ofhydrogen, alkyl, alkenyl, aryl, alkylaryl, and arylalkyl.

According to a furthermore specific embodiment, R¹ and R² are eachindependently selected from the group consisting of hydrogen, alkyl,aryl and alkenylaryl groups; and the groups are optionally substitutedby at least one halo group.

According to a furthermore specific embodiment, thealpha-hydroxy-beta-azido tetrazole is selected from the group consistingof:

-   2-azido-2-phenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;-   2-azido-2-(naphthalen-2-yl)-1-(1H-tetrazol-5-yl)ethan-1-ol;-   2-azido-2-(4-chlorophenyl)-1-(1H-tetrazol-5-yl)ethan-1-ol;-   2-azido-1-(1H-tetrazol-5-yl)-2-(thiophen-2-yl)ethan-1-ol;-   2-azido-4-phenyl-1-(1H-tetrazol-5-yl)but-3-en-1-ol;-   2-azido-1-(1H-tetrazol-5-yl)nonan-1-ol;-   2-azido-2-ethyl-1-(1H-tetrazol-5-yl)butan-1-ol; and-   2-azido-2,2-diphenyl-1-(1H-tetrazol-5-yl)ethan-1-ol.

According to an embodiment, R¹ and R² form together a group beinghydrocarbyl, aryl, heteroaryl, hydrocarbylaryl, arylhydrocarbyl,hydrocarbylheteroaryl, or heteroarylhydrocarbyl; and

the group is optionally substituted by at least one group beinghydrocarbyl, aryl, heteroaryl, oxo, hydroxyl, amido, amino, nitro,carboxylo, formyl, halo, thioxo or sulfhydryl; andthe group is optionally interrupted or terminated by at least one groupbeing —O—; —S—; and —NR^(N)— with R^(N) being hydrogen, hydrocarbyl,aryl, or a combination thereof; andthe nitrogen or sulfur atoms substituting or comprised in the group areoptionally oxidized.

According to a specific embodiment, R¹ and R² form together a groupselected from the group consisting of alkyl, alkenyl, aryl, alkylaryl,arylalkyl, alkenylaryl and arylalkenyl;

the group is optionally substituted by at least one group selected fromthe group consisting of hydroxyl, alkyl, alkenyl, aryl, alkylaryl,arylalkyl, amino, nitro, halo and sulfhydryl; andthe group is optionally interrupted or terminated by at least one groupselected from the group consisting of —O—; —S—; and —NR^(N)— with R^(N)being selected from the group consisting of hydrogen, alkyl, alkenyl,aryl, and a combination thereof.

According to a more specific embodiment, R¹ and R² form together a groupselected from the group consisting of alkyl, alkylaryl and arylalkyl;and the group is optionally substituted by at least one group selectedfrom the group consisting of hydroxyl, alkyl, amino, nitro and halo; andthe group is optionally interrupted or terminated by at least one groupselected from the group consisting of —O— and —NR^(N)— with R^(N) beingselected from the group consisting of hydrogen, alkyl, alkenyl, aryl,alkylaryl, and arylalkyl.

According to a furthermore specific embodiment, R¹ and R² form togethera group selected from the group consisting of alkyl and aryl.

According to a furthermore specific embodiment, alpha-hydroxy-beta-azidotetrazole is:

-   (1-azidocyclopentyl)(1H-tetrazol-5-yl)methanol;-   (1-azidocyclohexyl)(1H-tetrazol-5-yl)methanol;-   (1-azidocycloheptyl)(1H-tetrazol-5-yl)methanol;-   (1-azidocyclooctyl)(1H-tetrazol-5-yl)methanol; or-   (9-azido-9H-fluoren-9-yl)(1H-tetrazol-5-yl)methanol.

According to an embodiment, one or more amino, hydroxyl, or sulfhydrylgroup being present in compound (I) is protected by any suitableprotecting group known by a skilled person of the art.

According to a specific embodiment, one or more amino group beingpresent in compound (I) is protected by a protective group selectedfrom: benzyl (CH₂Ph), p-methoxybenzyl ether (PMB), tert-butyloxycarbonyl(BOC), carbobenzoyloxy (Cbz) and tosyl (Ts).

According to a specific embodiment, one or more hydroxyl group beingpresent in compound (I) is protected by a protective group being benzyl(CH₂Ph), p-methoxybenzyl ether (PMB), tetrahydropyranyl (THP) and silylethers such as trimethylsilyl (TMS, SiMe₃), tert-butyldimethylsilyl(TBDMS, SitBu(Me)₂), triethylsilyl (TES, SiEt₃), methyldiphenylsilyl(SiPh₂Me) or tri-isopropylsilyl (TIPS, Si(iPr)₃).

According to a specific embodiment, one or more sulfhydryl group beingpresent in compound (I) is protected by a protective group being benzyl(CH₂Ph), p-methoxybenzyl ether (PMB), triphenylmethyl ((C₆H₅)₃C) ortetrahydropyranyl (THP).

The alpha-hydroxy-beta-azido tetrazoles according to the invention maybe prepared by the process of manufacturing according to the invention,as disclosed hereafter.

The alpha-hydroxy-beta-azido tetrazoles according to the invention maybe used as reactants, as disclosed hereafter.

Synthesis of Alpha-Hydroxy-Beta-Azido Tetrazoles

The most popular way to efficiently produce tetrazoles is thecycloaddition of azides with nitriles. Various improvements haveappeared, including the use of sodium azide or trimethylsilyl azide(TMSN₃) with ammonium chloride, zinc dibromide, trimethyl aluminium, orsilver nitrate. However, these reactions are promoted either by Brønstedor Lewis acids and may thus be unsuitable for cycloaddition of sensiblenitriles. Some of the azide sources may also cause safety issues.Microwave irradiation has also been used, but this reaction requireselevated temperatures (above 100° C.).

Another possibility lies in the use of dibutyltin oxide (Bu₂SnO) as acatalyst, in conjunction with trimethylsilyl azide (TMSN₃), as describedby Wittenberger et al. (Wittenberger, S. J. et al., Journal of OrganicChemistry, 1993, Vol. 58, pp. 4139-4141.). In contrast to the abovemethods, this reaction involves neutral reaction medium and a weak Lewisacid, thus allowing cycloaddition of nitriles fitted with a Lewis base.This reaction has been applied to the synthesis of aryl tetrazoles andof unsubstituted aliphatic tetrazoles, but had never been applied to thesynthesis of alpha-hydroxy-beta-azido-tetrazoles.

In its second aspect, the invention relates to a process formanufacturing an alpha-hydroxy-beta-azido-tetrazole as disclosed inprevious section entitled “Alpha-hydroxy-beta-azido-tetrazoles”,comprising carrying out the reaction between an alpha, beta-epoxynitrileand an azide in presence of a catalyst.

According to an embodiment, the invention relates to a process formanufacturing an alpha-hydroxy-beta-azido tetrazole of formula (I):

comprising starting from an epoxynitrile of formula (II):

wherein R¹ and R² are each independently groups as disclosed in previoussection; or R¹ and R² form together a group as disclosed in previoussection;and performing the following steps:

-   -   (a) reacting compound (II) with an azide in presence of an        organometallic catalyst,    -   (b) performing a hydrolysis reaction to afford compound (I).

This process is schematically represented below:

Epoxynitriles compounds (II) can be synthesized by any suitable processknown by the skilled person of the art, e.g. by Darzens reaction asproposed by Arai et al. (Arai, S. et al., Tetrahedron Lett., 1995, 36,5417.).

According to an embodiment, the azide is organic, inorganic ororganometallic. According to a specific embodiment, the azide is sodiumazide or trimethylsilyl azide (TMSN₃). According to a more specificembodiment, the azide is trimethylsilyl azide.

According to an embodiment, the azide/epoxynitrile molar ratio in thereaction medium ranges from 20 to 1. According to a specific embodiment,the azide/epoxynitrile ratio ranges from 6 to 4. According to a morespecific embodiment, the azide/epoxynitrile ratio is about 3 (i.e. about3 equiv. of azide for 1 equiv. of epoxynitrile).

According to an embodiment, the catalyst is a metal oxide. According toa specific embodiment, the catalyst an dialkyltin oxide of generalformula (alkyl)₂SnO, such as dibutyltin oxide (Bu₂SnO) and dimethyltinoxide (Me₂SnO). According to a more specific embodiment, the catalyst isdibutyltin oxide.

According to an embodiment, the catalyst/epoxynitrile molar ratio in thereaction medium ranges from 5 to 0.01. According to another specificembodiment, the catalyst/epoxynitrile ratio ranges from 2 to 0.1.According to a more specific embodiment, the catalyst/epoxynitrile ratiois about 0.5 (i.e. about 0.5 equiv. of catalyst for 1 equiv. ofepoxynitrile).

According to an embodiment, the step of reacting an epoxynitrile with anazide is executed in a solvent. According to a specific embodiment, thesolvent is tetrahydrofurane (THF), chloroform, 1,2-dichloroethane,1,4-dioxane, toluene or mixtures thereof. According to a more specificembodiment, the solvent is toluene.

According to an embodiment, the step of reacting an epoxynitrile with anazide is executed in a duration ranging from 4 h to 72 h. According to aspecific embodiment, the duration ranges from 12 h to 24 h. According amore specific embodiment, the duration is about 18 h.

According to an embodiment, the step of reacting an epoxynitrile with anazide is executed at a temperature ranging from 25 to 100° C. Accordingto a specific embodiment, the temperature ranges from 40 to 80° C.According to a more specific embodiment, the temperature is about 60° C.

According to a specific embodiment, the hydrolysis reaction is an acidichydrolysis reaction. According to a specific embodiment, the reaction isperformed by using an acid being sulphuric acid, acetic acid,trifluoroacetic acid or hydrochloric acid (HCl); or aqueous solutionsthereof; or organic solutions thereof. According to a more specificembodiment, the hydrolysis is achieved through treatment by an aqueoushydrochloric acid solution, such as a 2N HCl solution.

According to a specific embodiment, the invention relates to a processfor manufacturing an alpha-hydroxy-beta-azido tetrazole of formula (I)as previously disclosed, comprising starting from an epoxynitrile offormula (II) as previously disclosed and performing the following steps:

-   -   (a) reacting compound (II) with TMSN₃ in toluene in presence of        Bu₂SnO,    -   (b) performing an acidic hydrolysis reaction to afford compound        (I).

According to an embodiment, the reaction between the epoxynitrile andthe azide is regioselective. According to an embodiment, the reactionbetween the epoxynitrile and the azide is stereoselective.

According to a specific embodiment, the reaction between theepoxynitrile and the azide is both regioselective and stereoselective.

Use of Alpha-Hydroxy-Beta-Azido-Tetrazoles in “Click” Reactions

The invention also relates to the use ofalpha-hydroxy-beta-azido-tetrazoles as reactants for synthesis,especially in “click” reactions such as CuAAC.

Alpha-Hydroxy-Beta-Triazolo-Tetrazoles—CuAAC Reaction

In its third aspect, the invention relates to analpha-hydroxy-beta-triazolo-tetrazole of formula (III):

wherein R¹ and R² are each independently groups as disclosed in previoussection; or R¹ and R² form together a group as disclosed in previoussection; andwherein R³ is hydrogen; an organic group such as alkyl, hydroxyl oramino; an organic molecule such as a polymer, a carbohydrate, a protein,an amino acid, a peptide, a nucleoside; an inorganic compound such as ametal salt; or an organometallic compound such as a metal complex.

The invention also relates to any stereoisomers, salts, solvates, andprodrugs of a compound of formula (III), including quaternary ammoniumsalts.

According to an embodiment, R³ is hydrogen, an organic group or anorganic molecule.

According to an embodiment, R³ is hydrogen, hydroxyl, amido, amino,cyano, tetrazolyl, triazolyl, nitro, carboxylo, formyl, halo orsulfhydryl.

According to an embodiment, R³ is any independent R¹ or R² group aspreviously disclosed.

According to an embodiment, R³ is hydrogen, hydrocarbyl, aryl,heteroaryl, hydrocarbylaryl, arylhydrocarbyl, hydrocarbylheteroaryl, orheteroarylhydrocarbyl group;

the group is optionally substituted by at least one group beinghydrocarbyl, aryl, heteroaryl, oxo, hydroxyl, amido, amino, azido,cyano, tetrazolyl, triazolyl, nitro, borono, carboxylo, formyl, halo,haloformyl, phosphono, phosphato, thioxo or sulfhydryl;the group is optionally interrupted or terminated by at least one groupbeing —B(OR^(B))— with R^(B) being hydrogen, hydrocarbyl, aryl or acombination thereof; —O—; —PR^(P)— with R^(P) being hydrogen,hydrocarbyl, aryl or a combination thereof; —P(OR^(OP))— with R^(OP)being hydrogen, hydrocarbyl, aryl or a combination thereof; —S—;—NR^(N)— with R^(N) being hydrogen, hydrocarbyl, aryl or a combinationthereof; or a combination thereof; andthe nitrogen, phosphorus or sulfur atoms substituting or comprised inthe group are optionally oxidized.

According to an embodiment, R³ is hydrogen, hydrocarbyl, aryl,heteroaryl, hydrocarbylaryl, arylhydrocarbyl, hydrocarbylheteroaryl, orheteroarylhydrocarbyl group;

the group is optionally substituted by at least one group beinghydrocarbyl, aryl, heteroaryl, oxo, hydroxyl, amido, amino, tetrazolyl,triazolyl, nitro, carboxylo, formyl, halo, thioxo or sulfhydryl; andthe group is optionally interrupted or terminated by at least one groupbeing —O—; —S—; and —NR^(N)— with R^(N) being hydrogen, hydrocarbyl,aryl, or a combination thereof; andthe nitrogen or sulfur atoms substituting or comprised in the group areoptionally oxidized.

According to a specific embodiment, R³ is selected from the groupconsisting of alkyl, alkenyl, aryl, heteroaryl, alkylaryl, arylalkyl,alkenylaryl, arylalkenyl, alkylheteroaryl, and heteroarylalkyl groups;and

the group is optionally substituted by at least one group selected fromthe group consisting of alkyl, alkenyl, aryl, heteroaryl, alkylaryl,arylalkyl, oxo, hydroxyl, amido, amino, tetrazolyl, triazolyl, nitro,carboxylo, formyl, halo, thioxo and sulfhydryl; andthe group is optionally interrupted or terminated by at least one groupselected from the group consisting of —O—; —S—; and —NR^(N)— with R^(N)being selected from the group consisting of hydrogen, alkyl, alkenyl,aryl, and a combination thereof.

According to a more specific embodiment, R³ is selected from the groupconsisting of alkyl, aryl, and alkylaryl groups; and the groups areoptionally substituted by at least one group selected from the groupconsisting of oxo, hydroxyl, alkyl, amino and halo; and the groups areoptionally interrupted or terminated by at least one group selected fromthe group consisting of —O— and —NR^(N)— with R^(N) being selected fromthe group consisting of hydrogen, alkyl, alkenyl, aryl, alkylaryl, andarylalkyl.

According to a furthermore specific embodiment, R³ is selected from thegroup consisting of alkyl and aryl; and the groups are optionallysubstituted by at least one group selected from the group consisting ofoxo, hydroxyl, alkyloxyl, and halo.

According to a furthermore specific embodiment, compound (III) isselected from the group consisting of:

-   (1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclohexyl)(1H-tetrazol-5-yl)methanol;-   (1-(4-phenyl-1H-1,2,3-triazol-1-yl)cycloheptyl)(1H-tetrazol-5-yl)methanol;-   (1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)(1H-tetrazol-5-yl)methanol;-   tert-butyl    1-(1-(hydroxy(1H-tetrazol-5-yl)methyl)cyclooctyl)-1H-1,2,3-triazole-4-carboxylate;-   (1-(4-(3-chloropropyl)-1H-1,2,3-triazol-1-yl)cyclooctyl)(1H-tetrazol-5-yl)methanol;-   2-(1-(1-(hydroxy(1H-tetrazol-5-yl)methyl)cyclooctyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol;-   2-ethyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-1-(1H-tetrazol-5-yl)butan-1-ol;-   2-(4-hexyl-1H-1,2,3-triazol-1-yl)-2-phenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;-   2-(4-hexyl-1H-1,2,3-triazol-1-yl)-2,2-diphenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;-   2-(4-(3-chloropropyl)-1H-1,2,3-triazol-1-yl)-2,2-diphenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;    and-   tert-butyl    1-(2-hydroxy-1,1-diphenyl-2-(1H-tetrazol-5-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate.

According to an embodiment, R³ is a carbohydrate, an amino acid, apeptide or a nucleoside.

According to an embodiment, one or more amino, hydroxyl or sulfhydrylgroup being present in compound (III) is protected by any suitableprotecting group known by a skilled person of the art. According to aspecific embodiment, one or more amino group being present in compound(III) is protected by a protective group being benzyl (CH₂Ph),p-methoxybenzyl ether (PMB), tert-butyloxycarbonyl (BOC),carbobenzoyloxy (Cbz) or tosyl (Ts). According to another specificembodiment, one or more hydroxyl group being present in compound (III)is protected by a protective group being benzyl (CH₂Ph), p-methoxybenzylether (PMB), tetrahydropyranyl (THP) or silyl ether such astrimethylsilyl (TMS, SiMe₃), tert-butyldimethylsilyl (TBDMS,SitBu(Me)₂), triethylsilyl (TES, SiEt₃), methyldiphenylsilyl (SiPh₂Me)or tri-isopropylsilyl (TIPS, Si(iPr)₃). According to another specificembodiment, one or more sulfhydryl group being present in compound (III)is protected by a protective group being benzyl (CH₂Ph), p-methoxybenzylether (PMB), triphenylmethyl ((C₆H₅)₃C) or tetrahydropyranyl (THP).

In its fourth aspect, the invention relates to a process formanufacturing a alpha-hydroxy-beta-triazolo-tetrazole, comprisingcarrying out the reaction between an alpha-hydroxy-beta-azido-tetrazoleand a terminal alkyne in presence of a copper(I) source and a tertiaryamine.

According to an embodiment, the invention relates to a process formanufacturing an alpha-hydroxy-beta-triazolo-tetrazole of formula (III):

comprising starting from an alpha-hydroxy-beta-azido-tetrazole offormula (I):

wherein R¹ and R² are each independently groups as previously disclosed;or R¹ and R² form together a group as previously disclosed;and a terminal alkyne of formula R³—C≡C—H,wherein R³ is as previously disclosed; andcarrying out the reaction of compound (I) with alkyne R³—C≡C—H inpresence of a copper(I) source and a tertiary amine, wherein thecopper(I) source is either:

-   -   a combination of a copper(I) salt and a base, or    -   a combination of a copper(II) salt and a reducing agent.

This process is schematically represented below (L referring to thetertiary amine):

According to an embodiment, the copper(I) salt is copper(I) chloride,copper(I) bromide (CuBr) or copper(I) acetate; and the base is a basicamine such as N,N-diisopropylethylamine (DIEA). According to a specificembodiment, the copper salt is copper(I) bromide and the base isN,N-diisopropylethylamine.

According to another embodiment, the copper(II) salt is copper(II)chloride, copper(II) bromide, copper(II) acetate or copper(II) sulphate(Cu^(II)SO₄); and the reducing agent is sodium ascorbate (NaAs) ortri(2-carboxyethyl)phosphine (TECP). According to a specific embodiment,the copper salt is copper(II) sulphate and the reducing agent is sodiumascorbate.

According to an embodiment, the tertiary amine istris(benzyltriazolylmethyl)amine (TBTA),tris(tertbutyltriazolylmethyl)amine (TTTA), tris(benzimidazole)methylamine (TBIA), 4,7-diphenyl-1,10-phenanthroline-disulfonic acid disodiumsalt, tris [2-(N,N-dibenzylamino)ethyl]amine ortris(benzyltriazolylmethyl)amine. According to a specific embodiment,the tertiary amine is tris(benzyltriazolylmethyl)amine (TBTA).

According to an embodiment, the alkyne/azide molar ratio in the reactionmedium ranges from 1 to 10. According to a specific embodiment, thealkyne/azide ratio ranges from 2 to 5. According to a more specificembodiment, the alkyne/azide ratio is about 3 (i.e. about 3 equiv. ofalkyne for 1 equiv. of azide).

According to an embodiment, the copper salt/azide molar ratio in thereaction medium ranges from 0.01 to 2. According to a specificembodiment, the copper salt/azide ratio ranges from 0.05 to 0.2.According to a more specific embodiment, the copper salt/azide ratio isabout 0.1 (i.e. about 0.1 equiv. of copper salt for 1 equiv. of azide).

According to an embodiment, the copper salt/tertiary amine molar ratioin the reaction medium ranges from 0.1 to 10. According to a specificembodiment, the copper salt/tertiary amine ratio ranges from 0.5 to 2.According to a more specific embodiment, the copper salt/tertiary amineratio is about 1 (i.e. about 1 equiv. of copper salt for 1 equiv. oftertiary amine).

According to an embodiment, the copper salt/reducing agent molar ratioin the reaction medium ranges from 0.1 to 2. According to a specificembodiment, the copper salt/reducing agent ratio ranges from 0.25 to0.75. According to a more specific embodiment, the copper salt/reducingagent ratio is about 0.5 (i.e. about 0.5 equiv. of copper salt for 1equiv. of reducing agent).

According to an embodiment, the step of carrying out the reactionbetween the alpha-hydroxy-beta-azido-tetrazole and the terminal alkyneis executed in a solvent. According to a specific embodiment, thesolvent is ethanol, tetrahydrofuran (THF), N,N′-dimethylformamide (DMF),acetonitrile, n-butyl alcohol (n-BuOH), water or mixtures thereof.According to a more specific embodiment, the solvent is a mixture ofn-butyl alcohol and water.

According to an embodiment, the step of carrying out the reactionbetween the alpha-hydroxy-beta-azido-tetrazole and the terminal alkyneis executed in a duration ranging from 12 h to 5 days. According to aspecific embodiment, the duration ranges from 24 h to 72 h. According amore specific embodiment, the duration is about 48 h.

According to an embodiment, the step of carrying out the reactionbetween the alpha-hydroxy-beta-azido-tetrazole and the terminal alkyneis executed at a temperature ranging from 0 to 50° C. According to aspecific embodiment, the temperature ranges from 15 to 30° C. Accordingto a more specific embodiment, the temperature is room temperature, i.e.about 25° C.

According to an embodiment, the step of carrying out the reactionbetween the alpha-hydroxy-beta-azido-tetrazole and the terminal alkyneis executed under a suitable inert gas, such as argon.

According to a specific embodiment, the invention relates to a processfor manufacturing a alpha-hydroxy-beta-triazolo-tetrazole of formula(III) as previously disclosed comprising starting from analpha-hydroxy-beta-azido-tetrazole of formula (I) and a terminal alkyneof formula R³—C≡C—H as previously disclosed, and carrying out thereaction of compound (II) with alkyne R³—C≡C—H in presence ofCu^(II)SO₄, TBTA and NaAs in a n-BuOH/H₂O mixture.

During the reaction described in this aspect of the invention, thehydroxy-tetrazole group acts as a “latent” or “hidden” alkyne group,meaning that it may be easily converted to an alkyne (as describedhereafter) but does not react under CuAAC conditions.

Triazole Alkynes—Hydroxy-Tetrazole to Alkyne Reaction

Wardrop et al. described the conversion of alpha-hydroxy-tetrazoles toalkynes through a [1,2]-rearrangement process using carbodiimides, whichare compounds of general formula RN═C═NR, as dehydrating agents(Wardrop, D. J. et al., Organic Letters, 2012, Vol. 14, No. 6, pp.1548-1551.). From alpha-hydroxy-alpha-aryl tetrazoles, this reactionallowed the preparation of internal alkynes substituted by at least onearyl group, most conveniently using diisopropylcarbodiimide (DIC).However, instead of forming this alkyne, this process could also lead toa 5-membered cycle or heterocycle, by a cyclisation mechanism involvingan [1,5]—C—H insertion.

In its fifth aspect, the invention relates to a triazole alkyne offormula (IV):

wherein R¹ and R² are each independent groups as disclosed in previoussection; or R¹ and R² form together a group as disclosed in previoussection; and R³ is as disclosed in previous section.

The invention also relates to any stereoisomers, salts, solvates, andprodrugs of a compound of formula (IV), including quaternary ammoniumsalts.

According to a furthermore specific embodiment, the triazole alkynesmanufactured by the process are selected from the group consisting of:

-   1-(1-ethynylcyclohexyl)-4-phenyl-1H-1,2,3-triazole;-   1-(1-ethynylcycloheptyl)-4-phenyl-1H-1,2,3-triazole;-   1-(1-ethynylcyclooctyl)-4-phenyl-1H-1,2,3-triazole;-   tert-butyl 1-(1-ethynylcyclooctyl)-1H-1,2,3-triazole-4-carboxylate;-   4-(3-chloropropyl)-1-(1-ethynylcyclooctyl)-1H-1,2,3-triazole;-   2-(1-(1-ethynylcyclooctyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol;-   1-(3-ethylpent-1-yn-3-yl)-4-phenyl-1H-1,2,3-triazole;-   4-hexyl-1-(1-phenylprop-2-yn-1-yl)-1H-1,2,3-triazole; and-   1-(1,1-diphenylprop-2-yn-1-yl)-4-hexyl-1H-1,2,3-triazole.

In its sixth aspect, the invention relates to a process formanufacturing a triazole alkyne, comprising carrying out the reactionbetween an alpha-hydroxy-beta-triazolo-tetrazole and a carbodiimide.

According to an embodiment, the invention relates to a process formanufacturing a triazole alkyne of formula (IV):

comprising starting from an alpha-hydroxy-beta-triazolo-tetrazole offormula (III):

wherein R¹ and R² are each independent groups as previously disclosed;or R¹ and R² form together a group as previously disclosed; and R₃ is aspreviously disclosed; andcarrying out the reaction of compound (III) with a carbodiimide.

This process is schematically represented below:

According to an embodiment, the carbodiimide isN,N′-dicyclohexylcarbodiimide (DCC), N, N′-diisopropylcarbodiimide(DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), phenyl ethylcarbodiimide (PEC), phenyl isopropyl carbodiimide (PIC), tert-butylethyl carbodiimide (BEC) or tert-butyl methyl carbodiimide (BMC).According to a specific embodiment, the carbodiimide is EDC.

According to an embodiment, the carbodiimide/tetrazole molar ratio inthe reaction medium ranges from 0.5 to 5. According to a specificembodiment, the carbodiimide/tetrazole ratio ranges from 1 to 1.5.According to a more specific embodiment, the carbodiimide/tetrazoleratio is about 1.2 (i.e. about 1.2 equiv. of carbodiimide for 1 equiv.of tetrazole).

According to an embodiment, the step of carrying out the reactionbetween the alpha-hydroxy-beta-triazolo-tetrazole and the carbodiimideis executed in a solvent. According to a specific embodiment, thesolvent is: chloroform, 1,2-dichloroethane, dichloromethane or mixturethereof. According to a more specific embodiment, the solvent isdichloromethane.

According to an embodiment, the step of carrying out the reactionbetween the alpha-hydroxy-beta-triazolo-tetrazole and the carbodiimideis executed in a duration ranging from 4 h to 72 h. According to aspecific embodiment, the duration ranges from 12 h to 24 h. According amore specific embodiment, the duration is about 18 h.

According to an embodiment, the step of carrying out the reactionbetween the alpha-hydroxy-beta-triazolo-tetrazole and the carbodiimideis executed at a temperature ranging from 0 to 50° C. According to aspecific embodiment, the temperature ranges from 15 to 30° C. Accordingto a more specific embodiment, the temperature is room temperature, i.e.about 25° C.

According to a specific embodiment, the invention relates to a processfor manufacturing an triazole alkyne of formula (IV) as previouslydisclosed, comprising starting from analpha-hydroxy-beta-triazolo-tetrazole of formula (III) as previouslydisclosed, and carrying out the reaction of compound (III) with EDC indichloromethane.

The reaction described in this aspect of the invention allows theconversion of the hydroxy-tetrazole to an alkyne, revealing the “latent”or “hidden” alkyne group of the alpha-hydroxy-beta-azido-tetrazole.

Multi-Triazoles—Further CuAAC Reactions

In its seventh aspect, the invention relates to a process formanufacturing molecules comprising starting from a triazole alkyne offormula (IV), and carrying out the reaction of the compound (IV) with anazide.

Synthesis of Di-Triazoles

According to a first embodiment, the invention relates to a process formanufacturing a di-triazole of formula (V):

comprising starting from a triazole alkyne of formula (IV):

wherein R¹ and R² are each independent groups as previously disclosed;or R¹ and R² form together a group as previously disclosed; and R³ is aspreviously disclosed;and from an azide of formula R⁴—N₃,wherein R⁴ is any R³ group as previously disclosed; andcarrying out the reaction of compound (IV) with azide R⁴—N₃ in thepresence of a copper(I) source.

This process is schematically represented below:

In this first embodiment, the compounds and the conditions of the stepof reaction of compound (IV) with azide R⁴—N₃ may be as previouslydisclosed in any embodiment of previous paragraph entitled “CuAACreaction—Alpha hydroxy-beta-triazolo-tetrazoles”, except that thepresence of a tertiary amine ligand may not be required.

According to a specific embodiment, R⁴ is a carbohydrate.

According to a specific embodiment, R⁴ is a metal complex.

According to a specific embodiment, R⁴ is an alkyl or alkylaryl groupoptionally substituted by at least one group being alkyl, oxo, hydroxyl,tetrazolyl or halo and optionally interrupted or terminated by at leastone group being —O— or —NH—.

According to a more specific embodiment, the di-triazoles manufacturedby this process are selected from the group consisting of:

-   1-octyl-4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclohexyl)-1H-1,2,3-triazole;-   1-[bis(η5-cyclopentadienyl)iron]-4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclohexyl)-1H-1,2,3-triazole;-   2-(acetoxymethyl)-6-(4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclohexyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl    triacetate;-   methyl    2-((tert-butoxycarbonyl)amino)-3-(4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclohexyl)-1H-1,2,3-triazol-1-yl)propanoate;-   1-octyl-4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)-1H-1,2,3-triazole;-   ethyl    4-(4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)-1H-1,2,3-triazol-1-yl)butanoate;-   4-phenyl-1-(1-(1-(pyren-1-ylmethyl)-1H-1,2,3-triazol-4-yl)cyclooctyl)-1H-1,2,3-triazole;-   1-benzyl-4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)-1H-1,2,3-triazole;-   2-ethyl-2-(4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)-1H-1,2,3-triazol-1-yl)-1-(1H-tetrazol-5-yl)butan-1-ol.

Synthesis of Poly-Triazoles

According to a second embodiment, the invention relates to a process formanufacturing an alpha-hydroxy-tetrazole of formula (VI):

comprising starting from a triazole alkyne of formula (IV):

and from an alpha-hydroxy-beta-azido tetrazole of formula (I):

wherein R¹ and R² are each independent groups as previously disclosed;or R¹ and R² form together a group as previously disclosed; and R₃ is aspreviously disclosed;and carrying out the reaction of the compound (IV) with compound (I) inpresence of a copper(I) source and a tertiary amine.

According to a third embodiment, the invention relates to a process formanufacturing a poly-triazole compound of formula (VII):

comprising starting from a triazole alkyne of formula (IV):

and from an alpha-hydroxy-beta-azido tetrazole of formula (I):

wherein R¹ and R² are each independent groups as previously disclosed;or R¹ and R² form together a group as previously disclosed; and R₃ is aspreviously disclosed;and performing n iterations of the following steps (a) and (b):

-   -   (a) carrying out the reaction of the compound (IV) with        compound (I) in the presence of a copper(I) source and a        tertiary amine.    -   (b) carrying out the reaction of resulting compound with a        carbodiimide.

This process is schematically represented below (L referring to thetertiary amine):

According to a specific embodiment, n ranges from 0 to 100. According toa more specific embodiment, n ranges from 1 to 10. According to anothermore specific embodiment, n ranges from 2 to 5.

According to a more specific embodiment, the poly-triazoles manufacturedby this process are selected from the group consisting in:1-(3-ethylpent-1-yn-3-yl)-4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)-1H-1,2,3-triazole;1-(1-ethynylcyclooctyl)-4-(3-(4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)-1H-1,2,3-triazol-1-yl)pentan-3-yl)-1H-1,2,3-triazole;and1-benzyl-4-(1-(4-(3-(4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)-1H-1,2,3-triazol-1-yl)pentan-3-yl)-1H-1,2,3-triazol-1-yl)cyclooctyl)-1H-1,2,3-triazole.

In these second and third embodiments, the compounds and the conditionsof step (a) may be as previously disclosed in any embodiment of previousparagraph entitled “CuAAC reaction—Alphahydroxy-beta-triazolo-tetrazoles”.

In this third embodiment, the compounds and the conditions of steps (b)may be as previously disclosed in any embodiment of previous paragraphentitled “Triazole alkynes—Hydroxy-tetrazole to alkyne reaction”.

The triazole heterocycle is an analogue of the peptidic bound, thereforeoligomeric or polymeric compounds of general formula (VII) are peptidesanalogues. Such biomimetic compounds may thus present valuableapplications in medicinal chemistry, and more generally in thebiotechnologies field.

Examples

The present invention is further illustrated by the following examples.

General Materials and Methods Materials

Starting aldehydes, alkynes and ketones are commercially available fromordinary chemical compounds suppliers, and were purchased fromSigma-Aldrich, Alfa Aesar, Acros Organics or TCI Chemicals.

Azides were prepared using known methods of the literature: Octyl azide(Org. Biomol. Chem., 2012, 10, 5993-6002.), Ferrocenyl azide (J.Organometal. Chem., 1970, 23, 225-228.), Pyrene azide (J. Org. Chem.2008, 73, 8212-8218.), Methyl3-azido-2-(tertbutoxycarbonyl-amino)propanoate (Bioorg. Med. Chem.,2010, 18, 7338-7347.),2,3,4,6-Tetra-O-acetyl-1-azido-β-D-glucopyranoside (Tet. Lett. 2007 483953-3957.), Ethyl 4-azido-butyrate (Eur. J. Org. Chem., 2011,229-233.). Benzyl azide was purchased from Sigma-Aldrich.

Other reactants and solvent are commercially available from ordinarychemical compounds suppliers, and were purchased from Sigma-Aldrich,Alfa Aesar, Acros Organics or TCI Chemicals.

Methods

Column chromatography were performed on a silica gel 230-400 mesh byusing various mixtures of dichloromethane (DCM), ethyl acetate (EtOAc),methanol (MeOH), acetic acid (AcOH) and petroleum ether (PE). Thin Layerchromatographies (TLCs) were run on Kieselgel 60F₂₅₄ plates and revealedby UV light and potassium permanganate (epoxides) or ninhydrin (azidotetrazoles).

¹H and ¹³C NMR spectra were collected on a Bruker Avance spectrometerrespectively at 200 or 300 MHz and 75 MHz. Data are presented asfollows: chemical shift (in ppm on the δ scale relative to STMS=0),multiplicity (s=singlet, d=doublet, t=triplet, m=multiplet, b=broad),coupling constant (J/Hz), integration and attribution. High resolutionmass spectra (HR-MS) were obtained on a Waters Micromass Q-TofMicroinstrument. Melting points are uncorrected.

Example 1: Epoxynitriles

Hereafter are provided epoxynitriles according to the invention. R¹ andR² groups refer to formula (II):

# R¹ R² Formula Name  1 Ph H

trans-3- phenyloxirane-2- carbonitrile  2 Ph H

cis-3- phenyloxirane-2- carbonitrile  3 naphthalen- 2-yl H

trans-3- (naphthalen-2- yl)oxirane-2- carbonitrile  4 naphthalen- 2-yl H

cis-3-(naphthalen- 2-yl)oxirane-2- carbonitrile  5 4- chlorophenyl H

trans-3-(4- chlorophenyl) oxirane-2-carbonitrile  6 4- chlorophenyl H

cis-3-(4- chlorophenyl)oxirane- 2-carbonitrile  7 thiophenyl H

3-(thiophen-2- yl)oxirane-2- carbonitrile  8 styryl H

3-styryloxirane-2- carbonitrile  9 heptyl H

3-heptyloxirane-2- carbonitrile 10 Et Et

3,3-diethyloxirane- 2-carbonitrile 11 butyl (cyclopentyl)

1- oxaspiro[2.4]heptane- 2-carbonitrile 12 pentyl (cyclohexyl)

1- oxaspiro[2.5]octane- 2-carbonitrile 13 hexyl (cycloheptyl)

1- oxaspiro[2.6]nonane- 2-carbonitrile 14 heptyl (cyclooctyl)

1- oxaspiro[2.7]decane- 2-carbonitrile 15 Ph Ph

3,3- diphenyloxirane-2- carbonitrile 16 fluorenyl

spiro[fluorene-9,2′- oxirane]-3′- carbonitrile

These compounds may be prepared as disclosed in Example 2.

Example 2: Synthesis of Epoxynitriles Materials and Methods Procedure(a) for the Synthesis of Epoxynitriles:

A solution of starting aldehyde or ketone (1 mol equiv.) andchloroacetonitrile (1.2 equiv.) in THF (15 mL/10 mmol) was addeddropwise to a suspension of freshly crushed NaOH (3 equiv.) in THF (5mL/10 mmol of NaOH). The reaction was stirred at room temperature andfollowed by TLC until full conversion of the aldehyde or ketone. Water(100 mL) and dichloromethane (100 mL) were added to the reaction mixtureand the organic layer was washed with brine. The organic layer wasconcentrated under reduced pressure and the crude residue was purifiedby flash chromatography on silica gel or alumina.

Results

Hereafter are provided the yield and physical characterization ofepoxynitriles #1-16 according to the invention, prepared from theappropriate aldehyde or ketone, by the above procedure.

# Name Characterization Yield 1 trans-3- ¹H NMR (200 MHz, CDCl₃)δ7.45-7.40 (m, 3H), 7.35- 29% phenyloxirane-2- 7.25 (m, 2H), 4.30 (d, J= 1.8 Hz, 1H), 3.43 (d, J = 1.8 Hz, carbonitrile 1H). ¹³C NMR (75 MHz,CDCl₃) δ132.75, 129.84, 128.99, 125.66, 116.03, 58.49, 44.64. HRMS (ESI,TOF MS) m/z calculated for [M + Na]+: 168.0426, found: 168.0427. 2cis-3- ¹H NMR (200 MHz, CDCl₃) δ7.50-7.35 (m, 5H), 4.26 32%phenyloxirane-2- (d, J = 3.7 Hz, 1H), 3.79 (d, J = 3.7 Hz, 1H). ¹³C NMR(75 carbonitrile MHz, CDCl₃) δ131.41, 129.73, 128.70, 126.32, 115.07,57.72, 45.12. HRMS (ESI, TOF MS) m/z calculated for [M + Na]+: 168.0426,found: 168.0427. 3 trans-3- ¹H NMR (200 MHz, CDCl₃) δ 7.95-7.80 (m, 4H),7.60- 32% (naphthalen-2- 7.50 (m, 2H), 7.35-7.25 (m, 1H), 4.46 (d, J =1.7 Hz, yl)oxirane-2- 1H), 3.52 (d, J = 1.7 Hz, 1H). ¹³C NMR (75 MHz,carbonitrile CDCl₃) δ 133.87, 132.93, 130.04, 129.09, 127.98, 127.91,127.08, 126.98, 126.15, 121.84, 116.06, 58.79, 44.71. HRMS (ESI, TOF MS)m/z calculated for [M + H]+: 196.0762, found: 196.0759. 4 cis-3- ¹H NMR(200 MHz, CDCl₃) δ 7.80-7.00 (m, 4H), 7.65- 33% (naphthalen-2- 7.45 (m,3H), 4.43 (d, J = 3.7 Hz, 1H), 3.87 (d, J = 3.7 Hz, yl)oxirane-2- 1H).¹³C NMR (75 MHz, CDCl₃) δ133.89, 132.88, carbonitrile 128.81, 128.70,128.18, 127.90, 126.93, 126.76, 126.31, 122.99, 115.06, 57.96, 45.28.HRMS (ESI, TOF MS) m/z calculated for [M + H]+: 196.0762, found:196.0759. 5 trans-3-(4- ¹H NMR (200 MHz, CDCl₃) δ 7.39 (d, J = 8.5 Hz,2H), 14% chloro- 7.23 (d, J = 8.5 Hz, 2H), 4.29 (d, J = 1.7 Hz, 1H),3.41 (d, phenyl)oxirane- J = 1.7 Hz, 1H). ¹³C NMR (75 MHz, CDCl3)δ135.85, 2-carbonitrile 131.26, 129.28, 127.01, 115.73, 57.89, 44.66.HRMS (ESI, TOF MS): not detected. 6 cis-3-(4- ¹H NMR (200 MHz, CDCl₃) δ7.43 (d, J = 8.6 Hz, 2H) 28% chloro- 7.37 (d, J = 8.6 Hz, 2H), 4.25 (d,J = 3.7 Hz, 1H), 3.80 (d, phenyl)oxirane- J = 3.7 Hz, 1H). ¹³C NMR (75MHz, CDCl₃) δ135.74, 2-carbonitrile 129.96, 129.02, 127.71, 114.84,57.14, 45.11. HRMS (ESI, TOF MS): not detected. 7 3-(thiophen-2- ¹H NMR(200 MHz, CDCl₃) δ 7.40 (dd, J = 5.0, 1.2 Hz, 89% yl)oxirane-2-1H_(cis)), 7.36 (dd, J = 5.0, 0.9 Hz, 1H_(trans)), 7.29 (dd, J =carbonitrile 2.4, 1.9 Hz, 1H_(cis)), 7.22 (dd, J = 3.6, 0.8 Hz,1H_(trans)), 7.08 (dd, J = 5.4, 4.0 Hz, 1H_(cis)), 7.04 (dd, J = 5.0,3.6 Hz, 1H_(trans)), 4.54 (d, J = 1.8 Hz, 1H_(trans)), 4.45 (d, J = 3.5Hz, 1H_(cis)), 3.82 (d, J = 3.5 Hz, 1H_(cis)), 3.61 (d, J = 1.8 Hz,1H_(trans)). ¹³C NMR (75 MHz, CDCl₃) δ 135.86 (trans), 134.20 (cis),128.26 (trans), 127.75 (cis), 127.61 (trans), 127.45(cis), 127.10 (cis),127.03 (trans), 115.63 (trans), 115.12 (cis), 55.59 (trans), 54.89(cis), 45.82 (cis), 45.43(trans). HRMS (ESI, TOF MS) m/z calculated for[M + H]⁺: 152.0170, found: 152.0172. 8 3-styryloxirane-2- Transstereoisomer: ¹H NMR (300 MHz, CDCl₃) δ 7.26 31% carbonitrile (m, 5H),6.81 (d, J = 16.0 Hz, 1H), 5.67 (dd, J = 16.0, 7.8 Hz, 1H), 3.83 (dd, J= 7.8, 1.7 Hz, 1H), 3.32 (d, J = 1.8 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ138.21, 134.98, 129.13, 128.89, 126.84, 121.49, 116.20, 58.94, 43.31.Cis stereoisomer: ¹H NMR (300 MHz, CDCl₃) δ 7.33 (m, 5H), 6.92 (d, J =15.9 Hz, 1H), 5.98 (dd, J = 15.9, 8.1 Hz, 1H), 3.76 (dd, J = 8.1, 3.7Hz, 1H), 3.65 (d, J = 3.7 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 139.42,135.04, 129.12, 128.82, 126.97, 120.30, 115.54, 57.54, 43.64. HRMS (ESI,TOF MS) m/z calculated for [M + H]⁺: 172.0762, found: 172.0763. 93-heptyloxirane-2- Trans stereoisomer: ¹H NMR (300 MHz, CDCl₃) δ 3.3459% carbonitrile (td, J = 6.0, 1.9 Hz, 1H), 3.17 (d, J = 1.9 Hz, 1H),1.71- 1.20 (m, 12H), 0.89 (t, J = 6.5 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ116.80, 59.17, 40.95, 31.63, 31.01, 29.08, 29.02, 25.26, 22.57, 14.04.Cis stereoisomer: ¹H NMR (300 MHz, CDCl₃) δ 3.46 (d, J = 3.8 Hz, 1H),3.19 (td, J = 6.0, 3.7 Hz, 1H), 1.88- 1.17 (m, 12H), 0.90 (t, J = 6.6Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 115.94, 57.44, 41.74, 31.66, 29.75,29.15, 29.06, 25.72, 22.59, 14.07. HRMS (ESI, TOF MS) m/z calculated for[M + H]⁺: 168.1388, found: 168.1387. 10 3,3- ¹H NMR (300 MHz, CDCl₃) δ3.27 (s, 1H), 1.96-1.62 55% diethyloxirane-2- (m, 4H), 1.09 (td, J =7.5, 1.3 Hz, 3H), 0.92 (td, J = 7.5, carbonitrile 1.3 Hz, 3H). ¹³C NMR(75 MHz, CDCl₃) δ 116.48, 67.34, 46.21, 25.44, 25.12, 9.07, 8.31. HRMS(ESI, TOF MS) m/z calculated for [M + H]⁺: 126.0919, found: 126.0917. 111- ¹H NMR (300 MHz, CDCl₃) δ 3.46 (s, 1H), 2.17-1.60 82%oxaspiro[2.4]heptane- (m, 8H). ¹³C NMR (75 MHz, CDCl₃) δ 116.59, 71.43,2-carbonitrile 45.78, 31.84, 30.62, 25.33, 24.92. HRMS (ESI, TOF MS) m/zcalculated for [M + H]⁺: 124.0762, found: 124.0766. 12 1- ¹H NMR (300MHz, CDCl₃) δ 3.24 (s, 1H), 1.83-1.49 86% oxaspiro[2.5]octane- (m, 10H).¹³C NMR (75 MHz, CDCl₃) δ 116.27, 65.46, 2-carbonitrile 47.39, 33.17,31.07, 24.75, 24.58. HRMS (ESI, TOF MS) m/z calculated for [M + H]⁺:138.0919, found: 138.0913 13 1- ¹H NMR (300 MHz, CDCl₃) δ 3.25 (s, 1H),2.12-1.44 85% oxaspiro[2.6]nonane- (m, 12H). ¹³C NMR (75 MHz, CDCl₃) δ116.46, 66.79, 2-carbonitrile 48.58, 35.46, 33.17, 28.84, 28.68, 24.33,23.99. IR (cm⁻¹) ν_(max): 2930, 2859, 2244, 1468, 1448, 943. HRMS (ESI,TOF MS) m/z calculated for [M + H]⁺: 152.1075, found: 152.1071. 14 1- ¹HNMR (300 MHz, CDCl₃) δ 3.28 (s, 1H), 2.01-1.46 48% oxaspiro[2.7]decane-(m, 14H). ¹³C NMR (75 MHz, CDCl₃) δ 116.50, 66.29, 2-carbonitrile 49.11,33.76, 31.74, 26.45, 25.89, 24.96, 24.35, 22.69. HRMS (ESI, TOF MS) m/zcalculated for [M + H]⁺: 166.1232, found: 166.1233. 15 3,3- Mp: 75° C.¹H NMR (300 MHz, CDCl₃) δ 7.41-7.21 (m, 88% diphenyloxirane- 10H), 3.83(s, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 2-carbonitrile 136.44, 134.48,129.34, 129.32, 128.81, 128.65, 127.72, 127.34, 115.27, 67.68, 50.11.HRMS (ESI, TOF MS) m/z calculated for [M + H]⁺: 222.0919, found:222.0919. 16 spiro[fluorene- Mp: 122° C. ¹H NMR (300 MHz, CDCl₃) δ7.65-7.02 42% 9,2′-oxirane]-3′- (m, 8H), 4.12 (s, 1H). ¹³C NMR (75 MHz,CDCl₃) δ carbonitrile 141.57, 141.35, 137.30, 135.48, 130.86, 130.78,128.15, 127.99, 123.78, 121.55, 120.82, 120.78, 115.17, 67.20, 48.31.HRMS (ESI, TOF MS) m/z calculated for [M + H]⁺: 220.0762, found:220.0759.

Example 3: Alpha-Hydroxy-Beta-Azido Tetrazoles

Hereafter are provided alpha-hydroxy-beta-azido tetrazoles according tothe invention. R¹ and R² groups refer to formula (I):

# R¹ R² Formula Name 17 Ph H

anti-2-azido-2- phenyl-1-(1H- tetrazol-5-yl)ethan- 1-ol 18 Ph H

syn-2-azido-2- phenyl-1-(1H- tetrazol-5-yl)ethan- 1-ol 19 naphthalen-2-yl

anti-2-azido-2- (naphthalen-2-yl)- 1-(1H-tetrazol-5- yl)ethan-1-ol 20naphthalen- 2-yl H

syn-2-azido-2- (naphthalen-2-yl)- 1-(1H-tetrazol-5- yl)ethan-1-ol 21 4-chlorophenyl H

anti-2-azido-2-(4- chlorophenyl)-1- (1H-tetrazol-5- yl)ethan-1-ol 22 4-chlorophenyl H

syn-2-azido-2-(4- chlorophenyl)-1- (1H-tetrazol-5- yl)ethan-1-ol 23thiophenyl H

2-azido-1-(1H- tetrazol-5-yl)-2- (thiophen-2- yl)ethan-1-ol 24 styryl H

(E)-2-azido-4- phenyl-1-(1H- tetrazol-5-yl)but-3- en-1-ol 25 heptyl H

2-azido-1-(1H- tetrazol-5- yl)nonan-1-ol 26 Et Et

2-azido-2-ethyl-1- (1H-tetrazol-5- yl)butan-1-ol 27 butyl (cyclopentyl)

(1- azidocyclopentyl) (1H-tetrazol-5- yl)methanol 28 pentyl (cyclohexyl)

(1- azidocyclohexyl) (1H-tetrazol-5- yl)methanol 29 hexyl (cycloheptyl)

(1- azidocycloheptyl) (1H-tetrazol-5- yl)methanol 30 heptyl (cyclooctyl)

(1- azidocyclooctyl) (1H-tetrazol-5- yl)methanol 31 Ph Ph

2-azido-2,2- diphenyl-1-(1H- tetrazol-5-yl)ethan- 1-ol 32 fluorenyl

(9-azido-9H- fluoren-9-yl)(1H- tetrazol-5- yl)methanol

These compounds may be prepared as disclosed in Example 4.

Example 4: Synthesis of Alpha-Hydroxy-Beta-Azido-Tetrazoles Materialsand Methods Procedure (b) for the Synthesis ofAlpha-Hydroxy-Beta-Azido-Tetrazoles

A solution of epoxynitrile (1 equiv.), Bu₂SnO (0.5 equiv.) and TMSN₃ (3equiv.) in toluene (10 mL/mmol of epoxide) was stirred at 60° C. for 18h. The solvent was removed under reduced pressure and a 1:1 THF/2Naqueous HCl mixture (20 mL) was added to the crude and stirred for 30min. Water and EtOAc were added and the aqueous layer was extracted(EtOAc), washed with brine and dried over MgSO₄.

Evaporation gave a residue that was washed by trituration with smallportions of dichloromethane. Further purification could be done by flashchromatography over silica gel using dichloromethane/MeOH/Acetic acid:9/0.5/0.5 mixture as eluent (spots were revealed with ninhydrin).

Results

Hereafter are provided the yield and physical characterization ofalpha-hydroxy-beta-azido tetrazoles according to the invention, preparedby the above procedure.

Compounds #17-32 were respectively prepared from epoxynitriles #1-16disclosed in Examples 1 and 2.

# Name Characterization Yield 17 anti-2-azido-2- Mp: 175° C. ¹H NMR (300MHz, DMSO) δ7.40-7.20 85% phenyl-1-(1H- (m, 5H), 6.76 (dl, J = 4.9 Hz,1H), 5.33 (t, J = 5.3 Hz, tetrazol-5-yl)ethan- 1H), 5.16 (d, J = 6.0 Hz,1H). ¹³C NMR (75 MHz, 1-ol DMSO) δ156.76, 135.34, 128.31, 127.85, 67.58,67.39. HRMS (ESI, TOF MS) m/z calculated for [M + H]⁺: 232.0947, found:232.0950. 18 syn-2-azido-2- Mp: 176° C. ¹H NMR (300 MHz, DMSO)δ7.35-7.20 65% phenyl-1-(1H- (m, 5H), 6.88 (dl, J = 5.8 Hz, 1H), 5.28(t, J = 5.6 Hz, tetrazol-5-yl)ethan- 1H), 5.07 (d, 1H, J = 6.1 Hz). ¹³CNMR (75 MHz, 1-ol DMSO) δ135.71, 128.49, 127.89, 68.13, 68.05. HRMS(ESI, TOF MS) m/z calculated for [M + H]⁺: 232.0947, found: 232.0950. 19anti-2-azido-2- Mp: 211° C. (dec.). ¹H NMR (300 MHz, DMSO) δ8.00- 55%(naphthalen-2-yl)-1- 7.85 (m, 3H), 7.82 (s, 1H), 7.60-7.45 (m, 2H), 7.42(d, (1H-tetrazol-5- 1H, J = 8.6 Hz), 6.83 (dl, J = 4.7 Hz, 1H), 5.45 (t,J = 5.0 yl)ethan-1-ol Hz, 1H), 5.36 (d, J = 5.9 Hz, 1H). ¹³C NMR (75MHz, DMSO) δ132.95, 132.66, 132.44, 127.92, 127.50, 127.17, 126.42,126.36, 125.31, 67.78, 67.47. HRMS (ESI, TOF MS) m/z calculated for [M +H]⁺: 282.1103, found: 282.1101. 20 syn-2-azido-2- Mp: 209° C. (dec.). ¹HNMR (300 MHz, DMSO) δ7.90- 56% (naphthalen-2-yl)-1- 7.80 (m, 4H),7.60-7.40 (m, 4H), 5.41 (d, J = 6.4 Hz, (1H-tetrazol-5- 1H), 5.36 (d, J= 6.4 Hz, 1H). ¹³C NMR (75 MHz, yl)ethan-1-ol DMSO) δ133.26, 64, 132.44,128.02, 127.91, 127.51, 127.05, 126.46, 126.39, 125.35, 68.35, 68.11.HRMS (ESI, TOF MS) m/z calculated for [M + H]⁺: 282.1103, found:282.1101. 21 anti-2-azido-2-(4- Mp: 198° C. (dec.). ¹H NMR (300 MHz,DMSO) δ7.40 63% chlorophenyl)-1- (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5Hz, 2H), 6.82 (dl, (1H-tetrazol-5- J = 3.2 Hz, 1H), 5.34 (t, J = 4.9 Hz,1H), 5.22 (d, J = 5.7 yl)ethan-1-ol Hz, 1H). ¹³C NMR (75 MHz, DMSO)δ134.36, 132.93, 129.72, 128.27, 67.43, 66.75. HRMS (ESI, TOF MS) m/zcalculated for [M + H]⁺: 266.0560, found: 266.0557. 22 syn-2-azido-2-(4-Mp: 203° C. (dec.). ¹H NMR (300 MHz, DMSO) δ7.42 51% chlorophenyl)-1-(d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 6.91 (dl, (1H-tetrazol-5-J = 5.5 Hz, 1H), 5.29 (t, J = 5.3 Hz, 1H), 5.14 (d, J = 6.0yl)ethan-1-ol Hz, 1H). ¹³C NMR (75 MHz, DMSO) δ134.73, 133.03, 129.74,128.39, 67.93, 67.18. HRMS (ESI, TOF MS) m/z calculated for [M + H]⁺:266.0560, found: 266.0557. 23 2-azido-1-(1H- Mp: 125° C. ¹H NMR (300MHz, DMSO) δ 7.57 (d, J = 38% tetrazol-5-yl)-2- 5.1 Hz, 1H_(min)), 7.51(d, J = 5.1 Hz, 1H_(maj)), 7.19 (d, J = (thiophen-2- 2.8 Hz, 1H_(min)),7.12 (d, J = 2.8 Hz, 1H_(maj)), 7.07 (s, yl)ethan-1-ol 1H), 7.03 (dd, J= 5.1, 3.6 Hz, 1H_(min)), 6.99 (dd, J = 5.0, 3.6 Hz, 1H_(maj)), 5.45 (d,J = 4.8 Hz, 1H_(maj)), 5.36 (d, J = 4.5 Hz, 1H_(maj) + 1H_(min)), 5.32(d, J = 4.3 Hz, 1H_(min)). ¹³C NMR (75 MHz, DMSO) δ 156.94 (maj), 156.21(min), 137.18 (min), 136.35 (maj), 128.00 (maj), 127.84 (min), 127.34(min), 127.23 (maj), 126.51 (min), 67.93 (min), 67.54 (maj), 63.35(min), 63.32 (maj). HRMS (ESI, TOF MS) m/z calculated for [M + H]⁺:238.0511, found: 238.0514. 24 (E)-2-azido-4- Mp: 134° C. ¹H NMR (300MHz, DMSO) δ 7.52-7.23 52% phenyl-1-(1H- (m, 5H), 6.85 (s, 1H), 6.81 (d,J = 16.0 Hz, 1H_(min)), 6.69 tetrazol-5-yl)but-3- (d, J = 15.9 Hz,1H_(maj)), 6.38 (dd, J = 15.9, 8.0 Hz, en-1-ol 1H_(min)), 6.31 (dd, J =15.9, 8.0 Hz, 1H_(maj)), 5.25 (bm, 1H_(min)), 5.24 (bm, 1H_(maj)), 4.66(dd, J = 7.5, 4.5 Hz, 1H_(maj)), 4.58 (dd, J = 7.8, 4.4 Hz, 1H_(min)).¹³C NMR (75 MHz, DMSO) δ 156.33, 135.55 (min), 135.52 (maj), 135.07(maj), 134.89 (min), 128.69 (maj), 128.29 (min), 126.63 (min), 126.58(maj), 122.79 (min), 122.27 (maj), 67.34 (min), 67.08 (maj), 66.68(maj), 66.51(min). HRMS (ESI, TOF MS) m/z calculated for [M + H]⁺:258.1103, found: 258.1102. 25 2-azido-1-(lH- Mp: 146° C. ¹H NMR (300MHz, DMSO) δ 6.69 (s, 70% tetrazol-5-yl)nonan- 1H), 5.15 (d, J = 3.9 Hz,1H), 3.85-3.75 (m, 1H), 1-ol 1.60-1.10 (m, 12H), 0.89-0.79 (m, 3H). ¹³CNMR (75 MHz, DMSO) δ 156.27, 67.31, 65.57, 31.10, 29.01, 28.56, 28.45,25.51, 22.02, 13.88. HRMS (ESI, TOF MS) m/z calculated for [M + H]⁺:254.1729, found: 254.1732. 26 2-azido-2-ethyl-1- Mp: 128° C. ¹H NMR (300MHz, DMSO) δ 6.74 (d, J = 60% (1H-tetrazol-5- 4.3 Hz, 1H), 5.10 (d, J =4.2 Hz, 1H), 1.95-1.75 (m, yl)butan-1-ol 2H), 1.45-1.25 (m, 2H), 0.94(t, J = 7.3 Hz, 3H), 0.80 (t, J = 7.3 Hz, 3H). ¹³C NMR (75 MHz, DMSO) δ156.27, 68.60, 24.24, 23.04, 7.55, 7.36. HRMS (ESI, TOF MS) m/zcalculated for [M + H]⁺: 212.1260, found: 212.1262. 27 (1- Mp: 161° C.¹H NMR (300 MHz, DMSO) δ 6.78 (d, J = 53% azidocyclopentyl)(1 4.5 Hz,1H), 5.10 (d, J = 4.4 Hz, 1H), 1.97-1.75 (m, H-tetrazol-5- 2H),1.45-1.22 (m, 6H). ¹³C NMR (75 MHz, DMSO) δ yl)methanol 156.68, 75.15,70.60, 33.55, 33.11, 23.41, 23.30. HRMS (ESI, TOF MS) m/z calculated for[M + H]⁺: 210.1103, found: 210.1104. 28 (1- Mp: 175° C. ¹H NMR (300 MHz,DMSO) δ 6.80 (d, J = 75% azidocyclohexyl)(1 4.8 Hz, 1H), 5.06 (d, J =4.8 Hz, 1H), 2.23-0.91 (m, H-tetrazol-5- 10H). ¹³C NMR (75 MHz, DMSO) δ156.01, 71.40, yl)methanol 65.48, 30.23, 29.77, 24.54, 21.39, 21.14.HRMS (ESI, TOF MS) m/z calculated for [M + H]⁺: 224.1260, found:224.1264. 29 (1- Mp: 172° C. ¹H NMR (300 MHz, DMSO) δ 6.81 (d, J = 76%azidocycloheptyl)(1 4.8 Hz, 1H), 5.00 (d, J = 4.8 Hz, 1H), 2.19-1.04 (m,H-tetrazol-5- 12H). ¹³C NMR (75 MHz, DMSO) δ 156.21, 70.95, yl)methanol68.96, 33.67, 33.07, 28.91, 28.88, 21.75, 21.66. HRMS (ESI, TOF MS) m/zcalculated for [M + H]⁺: 238.1416, found: 238.1408. 30 (1- Mp: 186° C.¹H NMR (300 MHz, DMSO) δ 6.76 (d, J = 51% azidocyclooctyl)(1 4.6 Hz,1H), 5.06 (d, J = 4.6 Hz, 1H), 2.23-1.88 (m, H-tetrazol-5- 2H),1.77-1.18 (m, 12H). ¹³C NMR (75 MHz, DMSO) yl)methanol δ 156.26, 70.09,68.91, 29.79, 28.06, 27.71, 27.21, 24.10, 21.49, 21.26. HRMS (ESI, TOFMS) m/z calculated for [M + H]⁺: 252.1573, found: 252.1576. 312-azido-2,2- Mp: 205° C. ¹H NMR (300 MHz, DMSO) δ 7.63-7.29 61%diphenyl-1-(1H- (m, 5H), 7.22-6.99 (m, 6H), 6.39 (d, J = 4.2 Hz, 1H).tetrazol-5-yl)ethan- ¹³C NMR (75 MHz, DMSO) δ 155.27, 140.06, 128.56,1-ol 127.95, 127.93, 127.71, 127.25, 126.11, 74.31, 69.88. HRMS (ESI,TOF MS) m/z calculated for [M + H]⁺: 308.1260, found: 308.1252. 32(9-azido-9H- Mp: 213° C. ¹H NMR (300 MHz, DMSO) δ 7.82 (d, J = 61%fluoren-9-yl)(1H- 6.9 Hz, 2H), 7.57-7.35 (m, 6H), 7.31 (d, J = 5.0 Hz,tetrazol-5- 1H), 5.68 (d, J = 4.8 Hz, 1H). ¹³C NMR (75 MHz, yl)methanolDMSO) δ 155.35 141.47, 140.69, 140.13, 139.92, 129.87, 127.94, 127.81,125.47, 125.14, 120.44, 74.21, 69.45. HRMS (ESI, TOF MS) m/z calculatedfor [M + H]⁺: 306.1103, found: 306.1111.

These results evidence that the applicant successfully conceived andreduced to practice an efficient, straightforward and stereospecificsynthesis of alpha-hydroxy-beta-azido tetrazoles.

Various combinations of R¹ and R² substituting groups were used,confirming that the scope of procedure (b) is very broad.

Example 5: Alpha-Hydroxy-Beta-Triazolo-Tetrazoles

Hereafter are provided alpha-hydroxy-beta-triazolo-tetrazoles accordingto the invention. R¹, R² and R³ groups refer to formula (III):

# R¹ R² R³ Formula Name 33 pentyl (cyclohexyl) Ph

(1-(4-phenyl-1H- 1,2,3-triazol-1- yl)cyclohexyl)(1H- tetrazol-5-yl)methanol 34 hexyl (cycloheptyl) Ph

(1-(4-phenyl-1H- 1,2,3-triazol-1- yl)cycloheptyl)(1H- tetrazol-5-yl)methanol 35 heptyl (cyclooctyl) Ph

(1-(4-phenyl-1H- 1,2,3-triazol-1- yl)cyclooctyl)(1H- tetrazol-5-yl)methanol 36 heptyl (cyclooctyl) —COOtBu

tert-butyl 1-(1- (hydroxy(1H- tetrazol-5- yl)methyl)cyclo-octyl)-1H-1,2,3- triazole-4- carboxylate 37 heptyl (cyclooctyl) 3-chloropropyl

(1-(4-(3- chloropropyl)-1H- 1,2,3-triazol-1- yl)cyclooctyl)(1H-tetrazol-5- yl)methanol 38 heptyl (cyclooctyl) 2- hydroxyethyl

2-(1-(1- (hydroxy(1H- tetrazol-5- yl)methyl)cyclo- octyl)-1H-1,2,3-triazol-4-yl)ethan- 1-ol 39 Et Et Ph

2-ethyl-2-(4- phenyl-1H-1,2,3- triazol-1-yl)-1-(1H- tetrazol-5-yl)butan-1-ol 40 Ph H hexyl

2-(4-hexyl-1H- 1,2,3-triazol-1-yl)- 2-phenyl-1-(1H- tetrazol-5-yl)ethan-1-ol 41 Ph Ph hexyl

2-(4-hexyl-1H- 1,2,3-triazol-1-yl)- 2,2-diphenyl-1- (1H-tetrazol-5-yl)ethan-1-ol 42 Ph Ph 3- chloropropyl

2-(4-(3- chloropropyl)-1H- 1,2,3-triazol-1-yl)- 2,2-diphenyl-1-(1H-tetrazol-5- yl)ethan-1-ol 43 Ph Ph —COOtBu

tert-butyl 1-(2- hydroxy-1,1- diphenyl-2-(1H- tetrazol-5-yl)ethyl)-1H-1,2,3-triazole- 4-carboxylate

These compounds may be prepared as disclosed in Example 6.

Example 6: CuAAC Synthesis of Alpha-Hydroxy-Beta-Triazolo-TetrazolesMaterials and Methods Procedures for the Synthesis ofAlpha-Hydroxy-Beta-Tetrazo-Tetrazoles Procedure (c):

The alpha-hydroxy-beta-azido-tetrazole substrate (1 mmol) was dissolvedin n-BuOH (3 mL). An alkyne (3 mmol) and TBTA(tris((1-benzyl-1H-1,2,3-triazolyl)methyl)amine) (0.1 mmol) were added.A solution of sodium ascorbate (0.2 mmol in 1.5 mL water) was added,followed by a solution of copper sulphate (0.1 mmol in 1.5 mL water).The mixture was stirred at room temperature for 48 hours. The organicphase was separated and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel.

Procedure (d):

A mixture of alpha-hydroxy-beta-azido-tetrazole substrate (0.10 mmol),copper (I) bromide (0.01 mmol) and TBTA (0.011 mmol) in THF (1 mL) wasplaced under argon atmosphere. An alkyne (0.30 mmol) anddiisopropylethylamine (0.05 mL, 0.30 mmol) were added, and the mixturewas stirred for 24 hours. The mixture was concentrated under reducedpressure. The residue was purified by flash chromatography on silicagel.

Results

Hereafter are provided the yield and physical characterization ofalpha-hydroxy-beta-triazolo-tetrazoles according to the invention,prepared by procedure (c) above. Compound #35 was also prepared byprocedure (d).

Compounds #33-43 were prepared from the correspondingalpha-hydroxy-beta-azido-tetrazoles disclosed in Example 3 and 4 andfrom the appropriate R³—C≡CH terminal alkyne.

# Name Characterization Yield 33 (1-(4-phenyl-1H- Mp: 210-212° C. ¹H NMR(300 MHz, DMSO-d6) δ 8.60 84% 1,2,3-triazol-1- (s, 1H), 7.87 (m, 2H),7.44 (m, 2H), 7.31 (m, 1H), 6.76 (c) yl)cyclohexyl)(1H- (d, J = 5.0 Hz,1H), 5.15 (d, J = 5.0 Hz, 1H), 2.61-2.66 tetrazol-5- (m, 2H), 1.88-1.96(m, 2H), 1.48-1.67 (m, 3H), 1.08-1.29 yl)methanol (m, 3H). ¹³C NMR (75MHz, DMSO-d6) δ 155.9, 145.6, 131.1, 128.7, 127.6, 125.1, 121.5, 70.9,66.3, 30.3, 24.3, 20.9, 20.8. HRMS (ESI, TOF MS) m/z calculated forC₁₆H₂₀N₇O [M + H]⁺: 326.1729, found: 326.1719. 34 (1-(4-phenyl-1H- Mp:119-120° C. ¹H NMR (300 MHz, DMF-d6) δ 8.74 (s, 98% 1,2,3-triazol-1-1H), 7.98 (m, 2H), 7.47 (m, 2H), 7.35 (m, 1H), 7.03 (bs, (c)yl)cycloheptyl)(1 1H), 5.46 (bs, 1H), 3.53 (bs, 1H), 2.32-2.36 (m, 2H),H-tetrazol-5- 1.88-1.96 (m, 2H), 1.45-1.54 (m, 8H). ¹³C NMR (75yl)methanol MHz, DMF-d6) δ 147.3, 132.8, 130.0, 129.8, 128.6, 126.3,122.6, 72.8, 71.9, 30.4, 23.2, 23.1, 21.7. HRMS (ESI, TOF MS) m/zcalculated for C₁₇H₂₂N₇O [M + H]⁺: 340.1886, found: 340.1893. 35(1-(4-phenyl-1H- Mp: 86-88° C. ¹H NMR (300 MHz, DMF-d6) δ 8.71 (s, 98%1,2,3-triazol-1- 1H), 7.96 (m, 2H), 7.44-7.49 (m, 2H), 7.34 (m,, 1H),(c) yl)cyclooctyl)(1H- 7.03 (bs, 1H), 5.48 (s, 1H), 3.66 (bs, 1H),2.52-2.72 (m, 90% tetrazol-5- 3H), 2.36-2.43 (m, 1H), 1.47-1.77 (m,12H). ¹³C NMR (d) yl)methanol (75 MHz, DMF-d6) δ 157.7, 146.9, 132.8,129.8, 128.6, 126.3, 122.7, 80.2, 71.7, 71.6, 29.3, 28.5, 25.7, 22.8.HRMS (ESI, TOF MS) m/z calculated for C₁₈H₂₄N₇O [M + H]⁺: 354.2042,found: 354.2045. 36 tert-butyl 1-(1- Mp: 118-120° C. ¹H NMR (300 MHz,DMSO-d6) δ 8.60 98% (hydroxy(1H- (s, 1H), 6.83 (bs, 1H), 5.25 (s, 1H),2.25-2.45 (m, 3H), (c) tetrazol-5- 1.26-1.66 (m, 20H). ¹³C NMR (75 MHz,DMSO-d6) δ yl)methyl)cyclo- 159.9, 139.5, 128.9, 81.1, 69.8, 29.1, 27.9,26.3, 24.2, octyl)-1H-1,2,3- 21.3. HRMS (ESI, TOF MS) m/z calculated fortriazole-4- C₁₇H₂₈N₇O₃ [M + H]⁺: 378.2254, found: 378.2257. carboxylate37 (1-(4-(3- Mp: 85-87° C. ¹H NMR (300 MHz, CDCl₃) δ 7.23 (s, 71%chloropropyl)-1H- 1H), 5.51 (s, 1H), 3.45 (t, J = 5.9 Hz, 1H), 2.67-2.79(m, (c) 1,2,3-triazol-1- 4H), 2.42-2.51 (m, 2H), 2.01-2.04 (m, 2H),1.47-1.82 (m, yl)cyclooctyl)(1H- 10H). ¹³C NMR (75 MHz, CDCl₃) δ 121.8,72.1, 71.3, tetrazol-5- 43.7, 31.6, 30.4, 29.6, 28.2, 27.3, 24.9, 22.1,22.0. HRMS yl)methanol (ESI, TOF MS) m/z calculated for C₁₅H₂₅N₇OCl [M +H]⁺: 354.1809, found: 354.1810. 38 2-(1-(1- ¹H NMR (300 MHz, CD₃OD) δ7.87 (s, 1H), 5.28 (s, 94% (hydroxy(1H- 1H), 3.83 (t, J = 6.7 Hz, 1H),2.90 (t, J = 6.5 Hz, 1H), (c) tetrazol-5- 2.30-2.61 (m, 4H), 1.43-1.57(m, 10H). ¹³C NMR (75 yl)methyl)cyclo- MHz, CDCl₃) δ 158.7, 145.3,124.4, 72.2, 72.0, 62.2, octyl)-1H-1,2,3- 30.9, 30.2, 30.0, 29.6, 28.8,26.0, 23.1. HRMS (ESI, TOF triazol-4-yl)ethan- MS) m/z calculated forC₁₄H₂₄N₇O₂ [M + H]⁺: 322.1991, 1-ol found: 322.1995. 39 2-ethyl-2-(4-Mp: 103-105° C. ¹H NMR (300 MHz, DMSO-d6) δ 8.56 99% phenyl-1H-1,2,3-(s, 1H), 7.87 (m, 2H), 7.43 (m,, 2H), 7.30 (m, 1H), 6.84 (c)triazol-1-yl)-1- (d, J = 5.4 Hz, 1H), 5.34 (d, J = 5.4 Hz, 1H),2.18-2.36 (1H-tetrazol-5- (m, 4H), 0.90 (t, J = 7.3 Hz, 3H), 0.83 (t, J= 7.4 Hz, yl)butan-1-ol 3H). ¹³C NMR (75 MHz, DMSO-d6) δ 156.2, 145.3,131.1, 128.7, 127.6, 125.1, 121.5, 69.9, 68.3, 24.6, 23.8, 7.5. HRMS(ESI, TOF MS) m/z calculated for C₁₅H₂₀N₇O [M + H]⁺: 314.1729, found:314.1724. 40 2-(4-hexyl-1H- Mp: 157-159° C. ¹H NMR (300 MHz, DMF-d6) δ8.32 78% 1,2,3-triazol-1- (bs, 1H), 7.30-7.53 (m, 5H), 6.37 (b, 2H),2.66 (t, J = 7.3 (c) yl)-2-phenyl-1- Hz, 1H), 1.61-1.64 (m, 2H), 1.30(b, 6H), 0.87 (t, J = 5.8 (1H-tetrazol-5- Hz, 1H). ¹³C NMR (75 MHz,DMF-d6) δ 136.7, 128.8, yl)ethan-1-ol 128.3, 122.2, 68.6, 66.9, 31.7,28.9, 25.7, 22.6, 13.8. HRMS (ESI, TOF MS) m/z calculated for C₁₇H₂₄N₇O[M + H]⁺: 342.2042, found: 342.2049. 41 2-(4-hexyl-1H- ¹H NMR (300 MHz,CDCl₃) δ 7.21-7.38 (m, 10H), 6.82- 60% 1,2,3-triazol-1- 6.93 (m, 3H),2.63-2.65 (m, 1H), 1.57 (m, 2H), 1.26 (b, (c) yl)-2,2-diphenyl- 6H),0.85 (t, J = 5.8 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) 1-(1H-tetrazol-5- δ162.8, 139.2, 138.4, 129.3, 128.7, 128.4, 127.8, 124.2, yl)ethan-1-ol71.4, 31.3, 28.9, 28.7, 25.2, 22.4, 13.9. HRMS (ESI, TOF MS) m/zcalculated for C₂₃H₂₈N₇O [M + H]⁺: 418.2355, found: 418.2353. 422-(4-(3- Mp: 114-116° C. ¹H NMR (300 MHz, CDCl₃) δ 7.25-7.39 78%chloropropyl)-1H- (m, 12H), 7.02 (bs, 1H), 6.83 (b, 4H), 3.55 (m, 2H),2.82 (c) 1,2,3-triazol-1- (m, 2H), 2.11 (m, 2H). ¹³C NMR (75 MHz, CDCl₃)δ yl)-2,2-diphenyl- 139.1, 138.3, 129.5, 128.8, 128.5, 127.8, 125.2,71.2, 1-(1H-tetrazol-5- 43.9, 31.4, 22.4. HRMS (ESI, TOF MS) m/zcalculated yl)ethan-1-ol for C₂₀H₂₁N₇OCl [M + H]⁺: 410.1496, found:410.1490. 43 tert-butyl 1-(2- Mp: 122-124° C. ¹H NMR (300 MHz, CDCl₃) δ7.69 (s, 49% hydroxy-1,1- 1H), 7.43 (b, 5H), 7.27 (b, 3H), 6.94-6.97 (m,3H), 1.59 (c) diphenyl-2-(1H- (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 159.2,155.5, tetrazol-5- 139.7, 138.1, 130.0, 129.5, 128.9, 128.8, 128.5,127.6, yl)ethyl)-1H- 83.1, 70.7, 27.9. HRMS (ESI, TOF MS) m/z calculated1,2,3-triazole-4- for C₂₂H₂₃N₇ONa [M + Na]⁺: 456.1760, found: 456.1754.carboxylate

These results evidence that the applicant successfully conceived andreduced to practice a CuAAC reaction between thealpha-hydroxy-beta-azido-tetrazoles and terminal alkynes.

Procedures (c) and (d) are thus efficient methods to prepare a widerange of alpha-hydroxy-beta-triazolo-tetrazoles compounds.

Example 7: Triazole Alkynes

Hereafter are provided triazoles alkynes according to the invention. R¹,R² and R³ groups refer to formula (IV):

# R¹ R² R³ Formula Name 44 pentyl (cyclohexyl) Ph

1-(1- ethynylcyclo- hexyl)- 4-phenyl-1H- 1,2,3-triazole 45 hexyl(cycloheptyl) Ph

1-(1- ethynylcyclo- heptyl)- 4-phenyl-1H- 1,2,3-triazole 46 heptyl(cyclooctyl) Ph

1-(1- ethynylcyclo- octyl)-4- phenyl-1H- 1,2,3-triazole 47 heptyl(cyclooctyl) tBuAc

tert-butyl 1-(1- ethynylcyclo- octyl)-1H- 1,2,3-triazole- 4-carboxylate48 heptyl (cyclooctyl) 3- chloropropyl

4-(3-chloro- propyl)- 1-(1- ethynylcyclo- octyl)-1H- 1,2,3-triazole 49heptyl (cyclooctyl) 2- hydroxy- ethyl

2-(1-(1- ethynylcyclo- octyl)-1H- 1,2,3-triazol- 4-yl)ethan- 1-ol 50 EtEt Ph

1-(3-ethylpent- 1-yn-3-yl)-4- phenyl-1H- 1,2,3-triazole 51 Ph H hexyl

4-hexyl-1-(1- phenylprop- 2-yn-1- yl)-1H-1,2,3- triazole 52 Ph Ph hexyl

1-(1,1- diphenylprop- 2-yn-1-yl)-4- hexyl-1H- 1,2,3-triazole

These compounds may be prepared as disclosed in Example 8.

Example 8: Synthesis of Triazole Alkenes Materials and Methods

Procedures for the Reaction of α-Hydroxy-β-Triazole-Tetrazoles withCarbodiimides:Procedure (e), with Diisopropylcarbodiimide (DIC):

The alpha-hydroxy-beta-triazole-tetrazole (0.35 mmol) was dissolved indichloromethane (10 mL). DIC (0.42 mmol) was added. The mixture wasstirred at room temperature for 18 hours, and then concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel.

Procedure (f), with N-(3-Dimethylaminopropyl)-N′-Ethylcarbodiimide(EDC):

The alpha-hydroxy-beta-triazole-tetrazole (0.1 mmol) was dissolved indichloromethane (5 mL). EDC (0.12 mmol) was added and the mixture wasstirred at room temperature for 18 hours. The mixture was diluted withdichloromethane and the resulting solution was washed successively withsolutions of aqueous 0.5M HCl, aqueous saturated NaCl and aqueoussaturated NaHCO₃. The organic layer was dried over MgSO₄ andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel.

Results

Hereafter are provided the yield and physical characterization oftriazole alkynes according to the invention, prepared by the aboveprocedures.

Compounds #44-52 were prepared from the correspondingalpha-hydroxy-beta-triazolo-tetrazoles disclosed in Example 5 and 6.

# Name Characterization Yield 44 1-(1- Mp: 114-116° C. ¹H NMR (300 MHz,CDCl₃) δ 8.18 (d, J = 69% ethynylcyclohexyl)- 4.6 Hz, 1H), 7.85-7.89 (m,2H), 7.26-7.47 (m, 3H), 2.78 (e) 4-phenyl-1H- (d, J = 4.7 Hz, 1H),2.25-2.43 (m, 4H), 1.77-1.88 (m, 1,2,3-triazole 5H), 1.28-1.43 (m, 1H).¹³C NMR (75 MHz, CDCl₃) δ 146.7, 130.7, 128.7, 128.0, 125.7, 118.5,82.4, 76.2, 61.5, 38.6, 24.7, 23.1. HRMS (ESI, TOF MS) m/z calculatedfor C₁₆H₁₈N₃ [M + H]⁺: 252.1501, found: 252.1498. 45 1-(1- Mp: 80-81° C.¹H NMR (300 MHz, CDCl₃) δ 8.18 (s, 61% ethynylcycloheptyl)- 1H), 7.85(m, 2H), 7.40-7.45 (m, 2H), 7.33 (m, 1H), 2.79 (e) 4-phenyl-1H- (s, 1H),2.59-2.63 (m, 2H), 2.27-2.34 (m, 2H), 1.66-1.87 1,2,3-triazole (m, 8H).¹³C NMR (75 MHz, CDCl₃) δ 146.5, 130.6, 128.7, 128.0, 125.7, 118.5,83.7, 75.4, 64.6, 42.1, 27.9, 22.7. HRMS (ESI, TOF MS) m/z calculatedfor C₁₇H₂₀N₃ [M + H]⁺: 266.1657, found: 266.1655. 46 1-(1- Mp: 78° C. ¹HNMR (300 MHz, CDCl₃) δ 8.15 (s, 1H), 73% ethynylcyclooctyl)- 7.85 (m,2H), 7.40-7.45 (m, 2H), 7.33 (t, J = 7.2 Hz, 1H), (e) 4-phenyl-1H- 2.72(s, 1H), 2.64-2.71 (m, 2H), 2.24-2.33 (m, 2H), 1.63- 1,2,3-triazole 1.81(m, 12H). ¹³C NMR (75 MHz, CDCl₃) δ 146.7, 130.6, 128.7, 128.0, 125.7,118.5, 83.9, 74.7, 64.3, 37.0, 27.7, 24.4, 22.4. HRMS (ESI, TOF MS) m/zcalculated for C₁₈H₂₂N₃ [M + H]⁺: 280.1814, found: 280.1817 47tert-butyl 1-(1- ¹H NMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 2.73 (s, 1H),76% ethynylcyclooctyl)- 2.57-2.62 (m, 2H), 2.18-2.24 (m, 2H), 1.61-1.75(m, (f) 1H-1,2,3- 21H). ¹³C NMR (75 MHz, CDCl₃) δ 160.2, 140.5, 130.6,triazole-4- 125.9, 83.1, 82.2, 75.2, 64.8, 37.0, 28.2, 27.6, 24.3, 22.3.carboxylate HRMS (ESI, TOF MS) m/z calculated for C₁₇H₂₆N₃O₂ [M + H]⁺:304.2025, found: 304.2031. 48 4-(3- ¹H NMR (300 MHz, CDCl₃) δ 7.69 (s,1H), 3.59 (t, J = 75% chloropropyl)-1- 6.4 Hz, 2H), 2.89 (t, J = 7.7 Hz,2H), 2.67 (s, 1H), 2.57- (f) (1- 2.64 (m, 2H), 2.16-2.26 (m, 4H),1.62-1.76 (m, 10H). ¹³C ethynylcyclooctyl)- NMR (75 MHz, CDCl₃) δ 145.6,119.9, 83.9, 74.4, 63.9, 1H-1,2,3- 44.3, 36.9, 31.9, 27.7, 24.3, 22.7,22.4. HRMS (ESI, TOF triazole MS) m/z calculated for C₁₅H₂₃N₃Cl [M +H]⁺: 280.1581, found: 280.1587. 49 2-(1-(1- ¹H NMR (300 MHz, CDCl₃) δ7.76 (s, 1H), 3.95 (t, J = 46% ethynylcyclooctyl)- 5.6 Hz, 1H),2.86-2.98 (m, 3H), 2.67 (s, 1H), 2.55-2.64 (f) 1H-1,2,3-triazol- (m,2H), 2.17-2.25 (m, 2H), 1.61-1.76 (m, 10H). ¹³C 4-yl)ethan-1-ol NMR (75MHz, CDCl₃) δ 144.5, 120.3, 83.8, 74.5, 64.0, 61.5, 36.9, 28.6, 27.7,24.3, 22.4. HRMS (ESI, TOF MS) m/z calculated for C₁₄H₂₂N₃O [M + H]⁺:248.1763, found: 248.1770. 50 1-(3-ethylpent-1- Mp: 36-38° C. ¹H NMR(300 MHz, CDCl₃) δ 8.17 (s, 73% yn-3-yl)-4- 1H), 7.87-7.90 (m, 2H),7.40-7.45 (m, 2H), 7.33 (m, 1H), (e) phenyl-1H-1,2,3- 2.79 (s, 1H),2.38-2.50 (m, 2H), 2.07-2.19 (m, 2H), 0.89 triazole (t, J = 7.4 Hz 6H).¹³C NMR (75 MHz, CDCl₃) δ 146.0, 130.7, 128.7, 127.9, 125.6, 120.6,81.2, 76.3, 66.0, 34.8, 8.5. HRMS (ESI, TOF MS) m/z calculated forC₁₅H₁₈N₃ [M + H]⁺: 240.1501, found: 240.1502 51 4-hexyl-1-(1- Mp: 59-61°C. ¹H NMR (300 MHz, CDCl₃) δ 7.37-7.48 75% phenylprop-2-yn- (m, 6H),6.67 (d, J = 2.0 Hz, 1H), 2.82 (d, J = 2.4 Hz, 1H), (e) 1-yl)-1H-1,2,3-2.68 (t, J = 7.5 Hz, 2H), 1.59-1.69 (m, 2H), 1.28-1.36 (m, triazole 6H),0.86 (t, J = 7.0 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 149.0, 135.6, 129.2,128.9, 127.0, 119.0, 78.1, 55.5, 31.4, 29.2, 28.8, 25.7, 22.5, 13.9.HRMS (ESI, TOF MS) m/z calculated for C₁₇H₂₂N₃ [M + H]⁺: 268.1814,found: 268.1812. 52 1-(1,1- Mp: 59-61° C. ¹H NMR (300 MHz, CDCl₃) δ7.25-7.44 62% diphenylprop-2- (m, 11H), 3.09 (s, 1H), 2.74 (t, J = 8.0Hz, 1H), 1.63-1.70 (f) yn-1-yl)-4-hexyl- (m, 2H), 1.29-1.33 (m, 6H),0.80 (b, 3H). ¹³C NMR (75 1H-1,2,3-triazole MHz, CDCl₃) δ 147.7, 140.3,128.8, 128.4, 127.9, 121.6, 83.2, 77.6, 69.1, 31.5, 29.3, 28.9, 25.7,22.5, 14.0. HRMS (ESI, TOF MS) m/z calculated for C₂₃H₂₆N₃ [M + H]⁺:344.2127, found: 344.2132.

Surprisingly, the formation of a 5-membered cycle or heterocycle wasnever observed by the applicant when carrying out the reaction ofalpha-hydroxy-beta-triazolo-tetrazoles with carbodiimides. The triazolesalkyne is thus the only product of the reaction.

These results evidence that the alpha-hydroxy-beta-triazolo-tetrazolesaccording to the invention may be efficiency converted to triazolesalkynes, by the very broad procedures (e) and (f) according to theinvention.

Example 9: Di-Triazoles and Synthesis Thereof Compounds

Hereafter are provided di-triazoles according to the invention. R¹, R²,R³ and R⁴ groups refer to formula (V):

# R¹ R² R³ R⁴ Formula Name 53 pentyl (cyclohexyl) Ph octyl

1-octyl-4-(1-(4- phenyl-1H-1,2,3- triazol-1- yl)cyclohexyl)-1H-1,2,3-triazole 54 pentyl (cyclohexyl) Ph bis(cyclo- pentadienyl)iron

1-[bis(η5- cyclopentadienyl) iron]-4-(1-(4- phenyl-1H-1,2,3- triazol-1-yl)cyclohexyl)- 1H-1,2,3-triazole 55 pentyl (cyclohexyl) Ph carbohydrate

(2S,3S,4R,5S,6S)- 2- (acetoxymethyl)- 6-(4-(1-(4- phenyl-1H-1,2,3-triazol-1- yl)cyclohexyl)- 1H-1,2,3-triazol- 1-yl)tetrahydro-2H-pyran-3,4,5- triyl triacetate 56 pentyl (cyclohexyl) Ph—CH₂CH(COOMe)NHBoc

methyl 2-((tert- butoxycarbonyl) amino)-3-(4-(1-(4- phenyl-1H-1,2,3-triazol-1- yl)cyclohexyl)- 1H-1,2,3-triazol- 1-yl)propanoate 57 heptyl(cyclooctyl) Ph octyl

1-octyl-4-(1-(4- phenyl-1H-1,2,3- triazol-1- yl)cyclooctyl)-1H-1,2,3-triazole 58 heptyl (cyclooctyl) Ph EtCOO-propyl

ethyl 4-(4-(1-(4- phenyl-1H-1,2,3- triazol-1- yl)cyclooctyl)-1H-1,2,3-triazol- 1-yl)butanoate 59 heptyl (cyclooctyl) Phpyren-1-ylmethyl

4-phenyl-1-(1-(1- (pyren-1- ylmethyl)-1H- 1,2,3-triazol-4-yl)cyclooctyl)- 1H-1,2,3-triazole 60 heptyl (cyclooctyl) Ph benzyl

1-benzyl-4-(1-(4- phenyl-1H-1,2,3- triazol-1- yl)cyclooctyl)-1H-1,2,3-triazole 61 heptyl (cyclooctyl) Ph —C(Et)₂—CH(OH)-Tz

2-ethyl-2-(4-(1- (4-phenyl-1H- 1,2,3-triazol-1- yl)cyclooctyl)-1H-1,2,3-triazol- 1-yl)-1-(1H- tetrazol-5- yl)butan-1-ol

Materials and Methods Procedure (g) for the CuAAC Reaction of TriazoleAlkynes:

The triazole alkyne substrate (0.1 mmol) was dissolved in n-BuOH (1 mL).An azide (0.3 mmol) was added. A solution of sodium ascorbate (0.02 mmolin 0.25 mL water) was added, followed by a solution of copper sulphate(0.01 mmol in 0.25 mL water). The mixture was stirred at roomtemperature for 48 hours. The organic phase was separated andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel.

Results

Hereafter are provided the yield and physical characterization ofdi-triazoles according to the invention, prepared by the above procedure(g).

Compounds #53-61 were prepared from the corresponding triazole alkynesdisclosed in Examples 7 and 8 and from the appropriate R⁴—N₃ azide.

# Name Characterization Yield 53 1-octyl-4-(1-(4- Mp: 110-112° C. ¹H NMRδ 7.93 (s, 1H), 7.81-7.84 (m, 98% phenyl-1H-1,2,3- 2H), 7.26-7.42 (m,4H), 4.26 (t, J = 6.9 Hz, 2H), 2.65- triazol-1- 2.80 (m, 4H), 1.84 (b,2H), 1.57-1.64 (m, 6H), 1.23-1.27 yl)cyclohexyl)-1H- (m, 10H), 0.85 (t,J = 6.1 Hz, 3H). ¹³C NMR (75 MHz, 1,2,3-triazole CDCl₃) δ 150.8, 147.2,130.5, 128.7, 128.0, 125.6, 121.1, 118.3, 62.3, 50.5, 35.7, 31.6, 30.1,28.9, 28.8, 26.4, 24.8, 22.5, 22.0, 14.0. HRMS (ESI, TOF MS) m/zcalculated for C₂₄H₃₅N₆ [M + H]⁺: 407.2923, found: 407.2924. 541-[bis(η5- Mp: 157-163° C. (dec.). ¹H NMR δ 7.92 (s, 1H), 7.80-7.83 75%cyclopentadienyl)iron]- (m, 2H), 7.27-7.40 (m, 4H), 5.22 (bs, 2H),4.14-4.24 (m, 4-(1-(4-phenyl- 9H), 2.65-2.75 (m, 4H), 1.84 (b, 2H),1.58-1.62 (m, 6H). 1H-1,2,3-triazol-1- ¹³C NMR (75 MHz, CDCl₃) δ 150.8,147.3, 130.6, 128.7, yl)cyclohexyl)-1H- 127.9, 125.5, 120.6, 118.3,80.4, 69.1, 68.8, 62.1, 50.1, 1,2,3-triazole 35.7, 24.8, 21.9. HRMS(ESI, TOF MS) m/z calculated for C₂₇H₂₈N₆Fe [M + H]⁺: 492.1724, found:492.1729. 55 2-(acetoxymethyl)- ¹H NMR δ 7.86-7.84 (m, 3H), 7.66 (s,1H), 7.30-7.42 (m, 93% 6-(4-(1-(4-phenyl- 3H), 5.82 (d, J = 9.0 Hz, 1H),5.23-5.39 (m, 2H), 5.33 (m, 1H-1,2,3-triazol-1- 1H), 4.27-4.33 (m, 1H),4.11-4.15 (m, 1H), 3.99-4.02 yl)cyclohexyl)-1H- (m, 1H), 2.70-2.81 (m,4H), 2.07 (s, 3H), 2.05 (s, 3H), 1,2,3-triazol-1- 2.01 (s, 3H), 1.84 (s,3H), 1.57-1.62 (m, 6H). ¹³C NMR yl)tetrahydro-2H- (75 MHz, CDCl₃) δ170.4, 169.8, 169.2, 168.8, 130.6, pyran-3,4,5- 128.7, 128.0, 125.5,120.5, 85.9, 75.2, 72.2, 70.6, 67.6, triyltriacetate 62.3, 61.4, 36.0,35.6, 24.8, 22.0, 21.9, 20.6, 20.4, 20.0. HRMS (ESI, TOF MS) m/zcalculated for C₃₀H₃₇N₆O₉ [M + H]⁺: 625.2622, found: 625.2626. 56 methyl2-((tert- ¹H NMR δ 7.81-7.89 (m, 3H), 7.29-7.41 (m, 4H), 5.42 89%butoxycarbonyl)amino)- (d, J = 6.9 Hz), 4.66-4.76 (m, 3H), 3.72 (s, 3H),2.61- 3-(4-(1-(4- 2.77 (m, 4H), 1.55-1.62 (m, 6H), 1.38 (s, 9H). ¹³C NMRphenyl-1H-1,2,3- (75 MHz, CDCl₃) δ 169.3, 154.9, 130.4, 128.7, 128.0,triazol-1- 125.6, 122.8, 118.4, 80.7, 62.2, 53.6, 53.0, 51.0, 35.8,yl)cyclohexyl)-1H- 35.7, 28.1, 24.8, 22.0. HRMS (ESI, TOF MS) m/z1,2,3-triazol-1- calculated for C₂₅H₃₄N₇O₄ [M + H]⁺: 496.2672, found:yl)propanoate 496.2669. 57 1-octyl-4-(1-(4- ¹H NMR δ 7.93 (s, 1H),7.80-7.83 (m, 2H), 7.27-7.41 (m, 92% phenyl-1H-1,2,3- 4H), 4.29 (t, J =6.9 Hz, 2H), 2.75-2.96 (m, 4H), 1.84- triazol-1- 1.89 (m, 2H), 1.65 (b,10H), 1.24-1.28 (m, 10H), 0.86 (t, yl)cyclooctyl)-1H- J = 6.1 Hz, 3H).¹³C NMR (75 MHz, CDCl₃) δ 151.2, 1,2,3-triazole 130.7, 128.7, 127.9,125.5, 121.3, 118.6, 66.1, 50.4, 33.5, 31.6, 30.0, 28.9, 28.8, 27.9,26.4, 24.6, 22.5, 22.0, 14.0. HRMS (ESI, TOF MS) m/z calculated forC₂₆H₃₈N₆Na [M + Na]⁺: 457.3056, found: 457.3061. 58 ethyl 4-(4-(1-(4- ¹HNMR δ 7.95 (s, 1H), 7.80-7.83 (m, 2H), 7.27-7.46 (m, 83%phenyl-1H-1,2,3- 4H), 4.38 (t, J = 6.7 Hz, 2H), 4.10 (m, 2H), 2.73-2.96(m, triazol-1- 4H), 2.15-2.35 (m, 4H), 1.64 (b, 10H), 1.23 (m, J = 6.5yl)cyclooctyl)-1H- Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 172.1, 151.2,1,2,3-triazol-1- 146.9, 130.6, 128.7, 127.9, 125.5, 121.7, 118.7, 66.1,yl)butanoate 60.7, 49.4, 33.5, 30.7, 27.9, 25.2, 24.6, 21.9, 14.1. HRMS(ESI, TOF MS) m/z calculated for C₂₄H₃₂N₆O₂Na [M + Na]⁺: 459.2484,found: 459.2479. 59 4-phenyl-1-(1-(1- ¹H NMR δ 8.02-8.25 (m, 8H),7.73-7.94 (m, 4H), 7.27- 100%  (pyren-1-ylmethyl)- 7.36 (m, 4H), 6.20(bs, 2H), 2.62-2.85 (m, 4H), 1.55 (b, 1H-1,2,3-triazol-4- 10H). ¹³C NMR(75 MHz, CDCl₃) δ 151.3, 132.2, 131.1, yl)cyclooctyl)-1H- 130.5, 129.0,128.7, 128.3, 128.0, 127.7, 127.2, 126.4, 1,2,3-triazole 126.3, 125.9,125.8, 125.6, 125.0, 124.9, 124.4, 121.7, 121.6, 118.7, 66.3, 52.6,33.3, 27.8, 24.6, 21.9. HRMS (ESI, TOF MS) m/z calculated for C₃₅H₃₂N₆Na[M + Na]⁺: 559.2586, found: 559.2584. 60 1-benzyl-4-(1-(4- Mp: 133-134°C. ¹H NMR δ 7.97 (s, 1H), 7.82-7.85 (m, 90% phenyl-1H-1,2,3- 2H),7.27-7.41 (m, 9H), 5.50 (bs, 2H), 2.73-2.95 (m, 4H), triazol-1- 1.65 (b,10H). ¹³C NMR (75 MHz, CDCl₃) δ 151.5, yl)cyclooctyl)-1H- 146.9, 134.1,130.5, 129.1, 128.7; 128.0, 127.9, 125.5, 1,2,3-triazole 121.5, 118.6,66.1, 54.2, 33.4, 27.9, 24.6, 21.9. HRMS (ESI, TOF MS) m/z calculatedfor C₂₅H₂₉N₆ [M + H]⁺: 413.2454, found: 413.2464 61 2-ethyl-2-(4-(1-(4-¹H NMR δ 8.59 (s, 1H), 8.33, (s, 1H), 8.18-8.21 (m, 2H), 91%phenyl-1H-1,2,3- 7.32-7.44 (m, 3H), 2.54-3.05 (m, 8H), 1.41-1.59 (b,triazol-1- 10H), 0.94-1.03 (m, 6H). ¹³C NMR (75 MHz, pyridine-yl)cyclooctyl)-1H- d₅) δ 151.2, 130.7, 128.7, 127.9, 125.5, 121.3,118.6, 1,2,3-triazol-1-yl)- 66.1, 50.4, 33.5, 31.6, 30.0, 28.9, 28.8,27.9, 26.4, 24.6, 1-(1H-tetrazol-5- 22.5, 22.0, 14.0. HRMS (ESI, TOF MS)m/z calculated yl)butan-1-ol for C₂₅H₃₅N₁₀O [M + H]⁺: 491.2995, found:491.2996.

These results evidence that the triazoles alkynes according to theinvention may be efficiency reacted with azides in CuAAC conditions toprepare various di-triazoles compounds.

Example 10: Poly-Triazoles and Synthesis Thereof Compounds

Hereafter are provided poly-triazoles according to the invention.

# Formula Name 62

1-(3-ethylpent-1-yn-3-yl)- 4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)- 1H-1,2,3-triazole 63

1-(1-ethynylcyclooctyl)-4- (3-(4-(1-(4-phenyl-1H- 1,2,3-triazol-1-yl)cyclooctyl)-1H-1,2,3- triazol-1-yl)pentan-3-yl)- 1H-1,2,3-triazole 64

1-benzyl-4-(1-(4-(3-(4-(1- (4-phenyl-1H-1,2,3- triazol-1-yl)cyclooctyl)-1H-1,2,3-triazol-1- yl)pentan-3-yl)-1H-1,2,3- triazol-1-yl)cyclooctyl)-1H-1,2,3-triazole

Materials and Methods Procedure for Synthesis of Bis-Triazole Alkyne#62:

2-Azido-2-ethyl-1-(1H-tetrazol-5-yl)-butan-1-ol (28 mg, 0.18 mmol) #26and 1-(1-ethynyl-cyclooctyl)-4-phenyl-1H-[1,2,3]triazole (45 mg, 0.16mmol) #46 were dissolved in nBuOH (2 mL). TBTA(tris((1-benzyl-1H-1,2,3-triazolyl)methyl)amine) (10.5 mg, 0.02 mmol)was added. A solution of sodium ascorbate (11 mg, 0.05 mmol in 0.5 mLwater) was added, followed by a solution of copper sulphate (5 mg, 0.02mmol in 0.5 mL water). The mixture was stirred at room temperature for48 hours. The mixture was concentrated under reduced pressure.

The residue was dissolved in 1,2-dichloroethane (3 mL). DIC (0.035 mL,0.22 mmol) was added. The mixture was stirred at 50° C. for 3 hours, andthen concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel using petroleum ether/EtOAc: 90/10 aseluent (Rf=0.18). The bis-triazole alkyne was isolated as a white solid(41 mg, 62% yield).

Procedure for Synthesis of Tris-Triazole Alkyne #63:

(1-Azido-cyclooctyl)-(1H-tetrazol-5-yl)-methanol (30 mg, 0.12 mmol) #30and the bis-triazole alkyne #62 (41 mg, 0.1 mmol) were dissolved inn-BuOH (2 mL) and THF (1 mL). TBTA(tris((1-benzyl-1H-1,2,3-triazolyl)methyl)amine) (8 mg, 0.015 mmol) wasadded. A solution of sodium ascorbate (7 mg, 0.035 mmol in 0.5 mL water)was added, followed by a solution of copper sulphate (3 mg, 0.012 mmolin 0.5 mL water). The mixture was stirred at room temperature for 5days. The mixture was concentrated under reduced pressure.

The residue was dissolved in 1,2-dichloroethane (2 mL). DIC (0.02 mL,0.14 mmol) was added. The mixture was stirred at room temperature for 4hours, and then concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel using petroleumether/EtOAc: 75/25 as eluent (Rf=0.27). The tris-triazole alkyne wasisolated as a white solid (31 mg, 52% yield).

Procedure for Synthesis of Tetra-Triazole #64:

The tris-triazole alkyne #63 (19 mg, 0.032 mmol) was dissolved in n-BuOH(1 mL). Benzyl azide (0.01 mL, 0.085 mmol) was added. A solution ofsodium ascorbate (3 mg, 0.015 mmol in 0.25 mL water) was added, followedby a solution of copper sulphate (1.2 mg, 0.005 mmol in 0.25 mL water).The mixture was stirred at room temperature for 24 hours. The mixturewas concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel using dichloromethane/MeOH: 98/2 aseluent (Rf=0.34). The tetra-triazole was isolated as white foam (20 mg,86% yield).

Results

Hereafter are provided the yield and physical characterization ofpoly-triazoles according to the invention, prepared by the aboveprocedures.

# Name Characterization Yield 62 1-(3-ethylpent-1- ¹H NMR (300 MHz,CDCl₃) δ 7.90 (s, 1H), 7.80-7.83 62% yn-3-yl)-4-(1-(4- (m, 3H),7.27-7.42 (m, 3H), 2.92-3.00 (m, 2H), 2.73-2.80 phenyl-1H-1,2,3- (m,2H), 2.72 (s, 1H), 2.28-2.40 (m, 2H), 2.03-2.14 (m, triazol-1- 2H), 1.66(b, 10H), 0.81 (m, 6H). ¹³C NMR (75 MHz, yl)cyclooctyl)- CDCl₃) δ 149.3,146.9, 130.7, 128.7, 127.9, 125.5, 122.6, 1H-1,2,3-triazole 118.5, 80.7,76.7, 66.2, 66.1, 34.7, 33.5, 27.9, 24.7, 22.0, 8.5. HRMS (ESI, TOF MS)m/z calculated for C₂₅H₃₂N₆Na [M + Na]⁺: 439.2586, found: 439.2585. 631-(1- ¹H NMR (300 MHz, CDCl₃) δ 7.91 (s, 1H), 7.79-7.82 52%ethynylcyclooctyl)- (m, 3H), 7.57 (s, 1H), 7.27-7.42 (m, 3H), 2.89-2.97(m, 4-(3-(4-(1-(4- 2H), 2.71-2.77 (m, 2H), 2.65 (s, 1H), 2.44-2.58 (m,6H), phenyl-1H-1,2,3- 2.15-2.22 (m, 2H), 1.61-1.74 (m, 20H), 0.76 (m,6H). ¹³C triazol-1- NMR (75 MHz, CDCl₃) δ 150.2, 147.9, 146.9, 130.6,yl)cyclooctyl)- 128.7, 127.9, 125.6, 121.0, 121.0, 118.7, 83.4, 75.0,67.0, 1H-1,2,3-triazol- 66.2, 64.4, 37.0, 33.5, 30.3, 27.9, 27.6, 24.7,24.3, 22.4, 1-yl)pentan-3-yl)- 22.0, 7.8. HRMS (ESI, TOF MS) m/zcalculated for 1H-1,2,3-triazole C₃₅H₄₇N₉Na [M + Na]⁺: 616.3852, found:616.3859. 64 1-benzyl-4-(1-(4- ¹H NMR (300 MHz, CDCl₃) δ 7.91 (s, 1H),7.80-7.82 86% (3-(4-(1-(4- (m, 2H), 7.57 (s, 1H), 7.51 (s, 1H),7.21-7.41 (m, 9H), phenyl-1H-1,2,3- 5.47 (s, 2H), 2.60-2.92 (m, 8H),2.38-2.51 (m, 4H), 1.52- triazol-1- 1.60 (m, 20H), 0.68-0.72 (m, 6H).¹³C NMR (75 MHz, yl)cyclooctyl)- CDCl₃) δ 151.1, 148.1, 142.4, 142.2,134.2, 130.5, 129.1, 1H-1,2,3-triazol- 128.8, 128.7, 128.0, 125.6,121.5, 121.3, 121.2, 118.9, 1-yl)pentan-3-yl)- 118.7, 67.0, 66.4, 54.2,33.6, 33.5, 30.3, 27.9, 27.8, 24.7, 1H-1,2,3-triazol- 24.6, 22.0, 21.9,7.8. HRMS (ESI, TOF MS) m/z 1-yl)cyclooctyl)- calculated for C₄₂H₅₅N₁₂[M + H]⁺: 727.4673, found: 1H-1,2,3-triazole 727.4678.

These results evidence that successive iterations of the reactionsaccording to the invention may be used to efficiently preparepoly-triazoles compounds substituted by different alkyl and aryl groups.

1. An alpha-hydroxy-beta-azido-tetrazole compound of formula (I):

wherein R¹ and R² are each independently selected from the groupsconsisting of hydrogen, hydrocarbyl, aryl, heteroaryl, hydrocarbylaryl,arylhydrocarbyl, hydrocarbylheteroaryl, and heteroarylhydrocarbylgroups; or R¹ and R² form together a hydrocarbyl, aryl, heteroaryl,hydrocarbylaryl, arylhydrocarbyl, hydrocarbylheteroaryl orheteroarylhydrocarbyl group; wherein the group is optionally substitutedby at least one hydrocarbyl, aryl, heteroaryl, oxo, hydroxyl, amido,amino, nitro, carboxylo, formyl, halo, thioxo or sulfhydryl; and whereinthe group is optionally interrupted or terminated by at least one of—O—, —S— or —NR^(N)—, wherein R^(N) is hydrogen, hydrocarbyl, aryl, or acombination thereof, and wherein the nitrogen and/or sulfur atoms areoptionally oxidized; or a stereoisomer, salt or solvent thereof.
 2. Thecompound according to claim 1, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, aryl,heteroaryl, alkylaryl, arylalkyl, alkenylaryl, and arylalkenyl groups;wherein the groups are optionally substituted by at least one hydroxyl,alkyl, alkenyl, aryl, alkylaryl, arylalkyl, amino, nitro, halo andsulfhydryl; and wherein the groups are optionally interrupted orterminated by at least one of —O—, —S—, and —NR^(N)—, wherein R^(N) isselected from the group consisting of hydrogen, alkyl, alkenyl, and acombination thereof.
 3. The compound according to claim 1, wherein R¹and R² are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, aryl, heteroaryl, alkylaryl and alkenylarylgroups; wherein the groups are optionally substituted by at least onehydroxyl, alkyl, amino, nitro, halo and sulfhydryl; and wherein thegroups are optionally interrupted or terminated by at least one of —O—,—S—, and —NR^(N)—, wherein R^(N) is selected from the group consistingof hydrogen, alkyl, alkenyl, aryl, alkylaryl, and arylalkyl.
 4. Thecompound according to claim 1, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen, alkyl, aryl andalkenylaryl groups; and the groups are optionally substituted by atleast one halo group.
 5. The compound according to claim 1, wherein R¹and R² form together a group selected from the group consisting ofalkyl, alkenyl, aryl, alkylaryl, arylalkyl, alkenylaryl and arylalkenyl;wherein the group is optionally substituted by at least one hydroxyl,alkyl, alkenyl, aryl, alkylaryl, arylalkyl, amino, nitro, halo andsulfhydryl; and wherein the group is optionally interrupted orterminated by at least one of —O—, —S—, and —NR^(N)—, wherein R^(N) isselected from the group consisting of hydrogen, alkyl, alkenyl, aryl,and a combination thereof.
 6. The compound according to claim 1, whereinR¹ and R² form together a group selected from the group consisting ofalkyl, alkylaryl and arylalkyl; wherein the group is optionallysubstituted by at least one hydroxyl, alkyl, amino, nitro and halo; andwherein the group is optionally interrupted or terminated by at leastone of —O— and —NR^(N)—, wherein R^(N) is selected from the groupconsisting of hydrogen, alkyl, alkenyl, aryl, alkylaryl, and arylalkyl.7. The compound according to claim 1, wherein R¹ and R² form together analkyl or aryl group.
 8. The compound according to claim 1, selected fromthe group consisting of:2-azido-2-phenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;2-azido-2-(naphthalen-2-yl)-1-(1H-tetrazol-5-yl)ethan-1-ol;2-azido-2-(4-chlorophenyl)-1-(1H-tetrazol-5-yl)ethan-1-ol;2-azido-1-(1H-tetrazol-5-yl)-2-(thiophen-2-yl)ethan-1-ol;2-azido-4-phenyl-1-(1H-tetrazol-5-yl)but-3-en-1-ol;2-azido-1-(1H-tetrazol-5-yl)nonan-1-ol;2-azido-2-ethyl-1-(1H-tetrazol-5-yl)butan-1-ol;2-azido-2,2-diphenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;(1-azidocyclopentyl) (1H-tetrazol-5-yl)methanol;(1-azidocyclohexyl)(1H-tetrazol-5-yl)methanol; (1-azidocycloheptyl)(1H-tetrazol-5-yl)methanol;(1-azidocyclooctyl)(1H-tetrazol-5-yl)methanol; and(9-azido-9H-fluoren-9-yl) (1H-tetrazol-5-yl)methanol.
 9. A process formanufacturing the compound of formula (I) according to claim 1, themethod comprising: starting from an epoxynitrile of formula (II):

and performing the following steps: (a) reacting the compound of formula(II) with an azide in presence of an organometallic catalyst, and (b)performing a hydrolysis reaction to afford compound (I).
 10. The processof claim 9, wherein the azide is trimethylsilyl azide.
 11. The processof claim 9, wherein the organometallic catalyst is dibutyltin oxide. 12.The process of claim 9, wherein step (a) is executed in a solvent, saidsolvent being toluene.
 13. The process of claim 9, wherein step (a) isexecuted at 60° C. for 18 h.
 14. The process of claim 9, wherein thehydrolysis of step (b) is acidic hydrolysis.
 15. Analpha-hydroxy-beta-triazole-tetrazole compound of formula (III):

wherein R¹ and R² are each independently selected from the groupconsisting of hydrogen, hydrocarbyl, aryl, heteroaryl, hydrocarbylaryl,arylhydrocarbyl, hydrocarbylheteroaryl, or heteroarylhydrocarbyl groups;or R¹ and R² form together a group being hydrocarbyl, aryl, heteroaryl,hydrocarbylaryl, arylhydrocarbyl, hydrocarbylheteroaryl, andheteroarylhydrocarbyl groups; wherein the group is optionallysubstituted by at least one hydrocarbyl, aryl, heteroaryl, oxo,hydroxyl, amido, amino, nitro, carboxylo, formyl, halo, thioxo orsulfhydryl; wherein the group is optionally interrupted or terminated byat least one of —O—, —S— or —NR^(N)—, wherein R^(N) is hydrogen,hydrocarbyl, aryl, or a combination thereof, and wherein the nitrogen orsulfur atoms are optionally oxidized; and wherein R³ is hydrogen, anorganic group or an organic molecule; or a stereoisomer, salt or solventthereof.
 16. The compound according to claim 15, wherein R³ is hydrogen,hydroxyl, amido, amino, cyano, tetrazolyl, triazolyl, nitro, borono,carboxylo, formyl, halo, haloformyl, phosphono, phosphate or sulfhydryl.17. The compound according to claim 15, wherein R³ is hydrogen,hydrocarbyl, aryl, heteroaryl, hydrocarbylaryl, arylhydrocarbyl,hydrocarbylheteroaryl, or heteroarylhydrocarbyl; wherein the group isoptionally substituted by at least one group being hydrocarbyl, aryl,heteroaryl, oxo, hydroxyl, amido, amino, cyano, tetrazolyl, triazolyl,nitro, carboxylo, formyl, halo, thioxo or sulfhydryl; wherein the groupis optionally interrupted or terminated by at least one of —O—, —S— or—NR^(N)—, wherein R^(N) is hydrogen, hydrocarbyl, aryl, or a combinationthereof, and wherein the nitrogen or sulfur atoms are optionallyoxidized.
 18. The compound according to claim 15, wherein R³ is acarbohydrate, an amino acid, a peptide or a nucleoside.
 19. The compoundaccording to claim 15, wherein R³ is selected from the group consistingof alkyl, alkenyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkenylaryl,arylalkenyl, alkylheteroaryl, and heteroarylalkyl groups; wherein thegroup is optionally substituted by at least one alkyl, alkenyl, aryl,heteroaryl, alkylaryl, arylalkyl, oxo, hydroxyl, amido, amino,tetrazolyl, triazolyl, nitro, carboxylo, formyl, halo, thioxo orsulfhydryl; and wherein the group is optionally interrupted orterminated by at least one of —O—, —S— or —NR^(N)—, wherein R^(N) isselected from the group consisting of hydrogen, alkyl, alkenyl, aryl,and a combination thereof.
 20. The compound according to claim 15,selected from the group consisting of:(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclohexyl)(1H-tetrazol-5-yl)methanol;(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cycloheptyl)(1H-tetrazol-5-yl)methanol;(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)(1H-tetrazol-5-yl)methanol;tert-butyl1-(1-(hydroxy(1H-tetrazol-5-yl)methyl)cyclooctyl)-1H-1,2,3-triazole-4-carboxylate;(1-(4-(3-chloropropyl)-1H-1,2,3-triazol-1-yl)cyclooctyl)(1H-tetrazol-5-yl)methanol;2-(1-(1-(hydroxy(1H-tetrazol-5-yl)methyl)cyclooctyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol;2-ethyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-1-(1H-tetrazol-5-yl)butan-1-ol;2-(4-hexyl-1H-1,2,3-triazol-1-yl)-2-phenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;2-(4-hexyl-1H-1,2,3-triazol-1-yl)-2,2-diphenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;2-(4-(3-chloropropyl)-1H-1,2,3-triazol-1-yl)-2,2-diphenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;and tert-butyl1-(2-hydroxy-1,1-diphenyl-2-(1H-tetrazol-5-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate.